Diaminopyrimidines as P2X3 and P2X2/3 modulators

ABSTRACT

Compounds and methods for treating diseases mediated by a P2X 3  and/or a P2X 2/3  receptor antagonist, the methods comprising administering to a subject in need thereof an effective amount of a compound of formula (I):  
                 
 
wherein D, X, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7  and R 8  are as defined herein.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is entitled to the benefit of provisional patentapplication Ser. No. 60/713,399 filed on Sep. 1, 2005, the disclosure ofwhich is incorporated herein by reference.

FIELD OF THE INVENTION

This invention pertains to compounds useful for treatment of diseasesassociated with P2X purinergic receptors, and more particularly to P2X₃and/or P2X_(2/3) antagonists usable for treatment of genitourinary,gastrointestinal, respiratory, and pain-related diseases, conditions anddisorders.

BACKGROUND OF THE INVENTION

The urinary bladder is responsible for two important physiologicalfunctions:

urine storage and urine emptying. This process involves two main steps:(1) the bladder fills progressively until the tension in its walls risesabove a threshold level; and (2) a nervous reflex, called themicturition reflex, occurs that empties the bladder or, if this fails,at least causes a conscious desire to urinate. Although the micturitionreflex is an autonomic spinal cord reflex, it can also be inhibited ormediated by centers in the cerebral cortex or brain.

Purines, acting via extracellular purinoreceptors, have been implicatedas having a variety of physiological and pathological roles. (See,Burnstock (1993) Drug Dev. Res. 28:195-206.) ATP, and to a lesserextent, adenosine, can stimulate sensory nerve endings resulting inintense pain and a pronounced increase in sensory nerve discharge. ATPreceptors have been classified into two major families, the P2Y- andP2X-purinoreceptors, on the basis of molecular structure, transductionmechanisms, and pharmacological characterization. TheP2Y-purinoreceptors are G-protein coupled receptors, while theP2X-purinoreceptors are a family of ATP-gated cation channels.Purinergic receptors, in particular, P2X receptors, are known to formhomomultimers or heteromultimers. To date, cDNAs for several P2Xreceptors subtypes have been cloned, including: six homomeric receptors,P2X₁; P2X₂; P2X₃; P2X₄; P2X₅; and P2X₇; and three heteromeric receptorsP2X_(2/3), P2X_(4/6), P2X_(1/5) (See, e.g., Chen, et al. (1995) Nature377:428-431; Lewis, et al. (1995) Nature 377:432-435; and Burnstock(1997) Neurophamacol. 36:1127-1139). The structure and chromosomalmapping of mouse genomic P2X₃ receptor subunit has also been described(Souslova, et al. (1997) Gene 195:101-111). In vitro, co-expression ofP2X₂ and P2X₃ receptor subunits is necessary to produce ATP-gatedcurrents with the properties seen in some sensory neurons (Lewis, et al.(1995) Nature 377:432-435).

P2X receptor subunits are found on afferents in rodent and human bladderurothelium. Data exists suggesting that ATP may be released fromepithelial/endothelial cells of the urinary bladder or other holloworgans as a result of distention (Burnstock (1999) J. Anatomy194:335-342; and Ferguson et al. (1997) J. Physiol. 505:503-511). ATPreleased in this manner may serve a role in conveying information tosensory neurons located in subepithelial components, e.g., suburotheliallamina propria (Namasivayam, et al. (1999) BJU Intl. 84:854-860). TheP2X receptors have been studied in a number of neurons, includingsensory, sympathetic, parasympathetic, mesenteric, and central neurons(Zhong, et al. (1998) Br. J. Pharmacol. 125:771-781). These studiesindicate that purinergic receptors play a role in afferentneurotransmission from the bladder, and that modulators of P2X receptorsare potentially useful in the treatment of bladder disorders and othergenitourinary diseases or conditions.

Recent evidence also suggests a role of endogenous ATP and purinergicreceptors in nociceptive responses in mice (Tsuda, et al. (1999) Br. J.Pharmacol. 128:1497-1504). ATP-induced activation of P2X receptors ondorsal root ganglion nerve terminals in the spinal cord has been shownto stimulate release of glutamate, a key neurotransmitter involved innociceptive signaling (Gu and MacDermott, Nature 389:749-753 (1997)).P2X₃ receptors have been identified on nociceptive neurons in the toothpulp (Cook et al., Nature 387:505-508 (1997)).

ATP released from damaged cells may thus lead to pain by activating P2X₃and/or P2X_(2/3) containing receptors on nociceptive sensory nerveendings. This is consistent with the induction of pain by intradermallyapplied ATP in the human blister-base model (Bleehen, Br J Pharmacol62:573-577 (1978)). P2X antagonists have been shown to be analgesic inanimal models (Driessen and Starke, Naunyn Schmiedebergs Arch Pharmacol350:618-625 (1994)). This evidence suggests that P2X₂ and P2X₃ areinvolved in nociception, and that modulators of P2X receptors arepotentially useful as analgesics.

There is accordingly a need for methods of treating diseases, conditionsand disorders mediated by P2X₃ and/or P2X_(2/3) receptors, as well as aneed for compounds that act as modulators of P2X receptors, includingantagonists of P2X₃ and P2X_(2/3) receptors. The present inventionsatisfies these needs as well as others.

Other researchers have shown that P2X₃ receptors are expressed in humancolon, and are expressed at higher levels in inflamed colon than innormal colon (Y. Yiangou et al, Neurogastroenterol Mot (2001)13:365-69). Other researchers have implicated the P2X₃ receptor indetection of distension or intraluminal pressure in the intestine, andinitiation of reflex contractions (X. Bian et al., J Physiol (2003)551.1:309-22), and have linked this to colitis (G. Wynn et al., Am JPhysiol Gastrointest Liver Physiol (2004) 287:G647-57).

Inge Brouns et al. (Am J Respir Cell Mol Biol (2000) 23:52-61) foundthat P2X₃ receptors are expressed in pulmonary neuroepithelial bodies(NEBs), implicating the receptor in pain transmission in the lung. Morerecently, others have implicated P2X₂ and P2X₃ receptors in pO₂detection in pulmonary NEBs (W. Rong et al., J Neurosci (2003) 23(36):11315-21).

SUMMARY OF THE INVENTION

The invention provides compounds of formula (I):

or pharmaceutically acceptable salts thereof,wherein:X is:

-   -   —CH₂—;    -   —O—;    -   —S(O)_(n)—;    -   or —NR^(c)—    -   wherein        -   n is from 0 to 2 and        -   R^(c) is hydrogen or alkyl;            D is an optional oxygen;            R¹ is:    -   alkyl;    -   alkenyl;    -   cycloalkyl;    -   cycloalkenyl;    -   halo;    -   haloalkyl; or    -   hydroxyalkyl;        R², R³, and R⁴ each independently is:    -   hydrogen;    -   alkyl;    -   alkenyl;    -   amino;    -   halo;    -   amido;    -   haloalkyl;    -   alkoxy;    -   hydroxy;    -   haloalkoxy;    -   nitro; amino;    -   hydroxyalkyl;    -   alkoxyalkyl;    -   hydroxyalkoxy;    -   alkynylalkoxy;    -   alkylsulfonyl;    -   arylsulfonyl;    -   cyano;    -   aryl;    -   heteroaryl;    -   heterocyclyl;    -   heterocyclylalkoxy;    -   aryloxy;    -   heteroaryloxy;    -   aralkyloxy;    -   heteroaralkyloxy;    -   optionally substituted phenoxy;    -   —C≡C—R^(a);    -   —(CH₂)_(m)-(Z)_(n)-(CO)—R^(b);    -   —(CH₂)_(m)-(Z)_(n)-SO₂—(NR^(c))_(n)—R^(b)    -   wherein        -   m and n each independently is 0 or 1,        -   Z is O or NR^(c),        -   R^(a) is hydrogen; alkyl; aryl; aralkyl; heteroaryl;            heteroaralkyl; hydroxyalkyl; alkoxyalkyl;            alkylsulfonylalkyl; aminoalkyl; cyanoalkyl; alkylsilyl,            cycloalkyl, cycloalkylalkyl; heterocycl; and            heterocyclylalkyl;        -   R^(b) is hydrogen, alkyl, hydroxy, alkoxy, amino,            hydroxyalkyl or alkoxyalkyl, and        -   each R^(c) is independently hydrogen or alkyl;    -   or R² and R³ together with the atoms to which they are attached        may form a five or six-membered ring that optionally includes        one or two heteroatoms selected from O, S and        N;        R⁵ is:    -   hydrogen;    -   alkyl;    -   aryl;    -   aralkyl;    -   heteroaryl;    -   heteroaralkyl;    -   hydroxyalkyl;    -   alkoxyalkyl;

alkylsulfonylalkyl;

-   -   aminoalkyl;    -   cyanoalkyl;    -   alkylsilyl,    -   cycloalkyl,    -   cycloalkylalkyl;    -   heterocycl; or    -   heterocyclylalkyl;        R⁶ is:    -   hydrogen;    -   alkyl;    -   halo;    -   haloalkyl;    -   amino; or    -   alkoxy; and        R⁷ and R⁸ each independently is:    -   hydrogen;    -   alkyl;    -   alkoxyalkyl;    -   aminoalkyl;    -   aminosulfonyl;    -   cycloalkyl;    -   cycloalkylalkyl;    -   haloalkyl;    -   haloalkoxy;    -   hydroxyalky;    -   alkoxyalkyl;    -   alkylsulfonyl;    -   alkylsulfonylalkyl;    -   aminocarbonyloxyalkyl;    -   hydroxycarbonylalkyl;    -   hydroxyalkyloxycarbonylalkyl;    -   aryl;    -   aralkyl;    -   arylsulfonyl;    -   heteroaryl;    -   heteroarylalkyl;    -   heteroarylsulfonyl;    -   heterocyclyl; or    -   heterocyclylalkyl.

The invention also provides and pharmaceutical compositions comprisingthe compounds, methods of using the compounds, and methods of preparingthe compounds.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

Unless otherwise stated, the following terms used in this Application,including the specification and claims, have the definitions givenbelow. It must be noted that, as used in the specification and theappended claims, the singular forms “a”, “an,” and “the” include pluralreferents unless the context clearly dictates otherwise.

“Agonist” refers to a compound that enhances the activity of anothercompound or receptor site.

“Alkyl” means the monovalent linear or branched saturated hydrocarbonmoiety, consisting solely of carbon and hydrogen atoms, having from oneto twelve carbon atoms. “Lower alkyl” refers to an alkyl group of one tosix carbon atoms, i.e. C₁-C₆alkyl. Examples of alkyl groups include, butare not limited to, methyl, ethyl, propyl, isopropyl, isobutyl,sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, and the like.

“Alkenyl” means a linear monovalent hydrocarbon radical of two to sixcarbon atoms or a branched monovalent hydrocarbon radical of three tosix carbon atoms, containing at least one double bond, e.g., ethenyl,propenyl, and the like.

“Alkynyl” means a linear monovalent hydrocarbon radical of two to sixcarbon atoms or a branched monovalent hydrocarbon radical of three tosix carbon atoms, containing at least one triple bond, e.g., ethynyl,propynyl, and the like.

“Alkylene” means a linear saturated divalent hydrocarbon radical of oneto six carbon atoms or a branched saturated divalent hydrocarbon radicalof three to six carbon atoms, e.g., methylene, ethylene,2,2-dimethylethylene, propylene, 2-methylpropylene, butylene, pentylene,and the like.

“Alkoxy” means a moiety of the formula —OR, wherein R is an alkyl moietyas defined herein. Examples of alkoxy moieties include, but are notlimited to, methoxy, ethoxy, isopropoxy, and the like.

“Alkoxyalkyl” means a moiety of the formula R^(a)—O—R^(b)—, where R^(a)is alkyl and R^(b) is alkylene as defined herein. Exemplary alkoxyalkylgroups include, by way of example, 2-methoxyethyl, 3-methoxypropyl,1-methyl-2-methoxyethyl, 1-(2-methoxyethyl)-3-methoxypropyl, and1-(2-methoxyethyl)-3-methoxypropyl.

“Alkylcarbonyl” means a moiety of the formula —R′—R″, where R′is oxo andR″ is alkyl as defined herein.

“Alkylsulfonyl” means a moiety of the formula —R′—R″, where R′ is —SO₂—and R″ is alkyl as defined herein.

“Alkylsulfonylalkyl means a moiety of the formula —R′—R″—R′″ where R′ isalkylene, R″ is —SO₂— and R′″ is alkyl as defined herein.

“Alkoxyamino” means a moiety of the formula —NR—OR′ wherein R ishydrogen or alkyl and R′ is alkyl as defined herein.

“Alkylsulfanyl” means a moiety of the formula —SR wherein R is alkyl asdefined herein.

“Amino” means a group —NR′R″ wherein R′ and R″ each independently ishydrogen or alkyl. “Amino” as used herein thus encompasses “alkylamino”and “dialkylamino”.

“Aminoalkyl” means a group —R—NR′R″ wherein R is alkylene, and R′ and R″each independently is hydrogen or alkyl. “Alkylamino” as used hereinthus encompasses “alkylaminoalkyl” and “dialkylaminoalkyl”.

“Aminosulfonyl” means a group —SO₂—NR′R″ wherein R′ and R″ eachindependently is hydrogen or alkyl. “Aminosulfonyl” as used herein thusencompasses “alkylaminosulfonyl” and “dialkylaminosulfonyl”.

“Alkylaminoalkyl” means a group —R—NHR′ wherein R is alkylene and R′ isalkyl. Alkylaminoalkyl includes methylaminomethyl, methylaminoethyl,methylaminopropyl, ethylaminoethyl and the like.

“Dialkylaminoalkyl” means a group —R—NR′R″ wherein R is alkylene and R′and R″ are alkyl as defined herein. Dialkylaminoalkyl includesdimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl,N-methyl-N-ethylaminoethyl, and the like.

“Aminoalkoxy” means a group —OR—R′ wherein R′ is amino and R is alkyleneas defined herein.

“Alkylsulfonylamido” means a moiety of the formula —NR′SO₂—R wherein Ris alkyl and R′ is hydrogen or alkyl.

“Aminocarbonyloxyalkyl” or “carbamylalkyl” means a group of the formula—R—O—C(O)—NR′R″ wherein R is alkylene and R′, R″ each independently ishydrogen or alkyl as defined herein.

“Alkynylalkoxy” means a group of the formula —O—R—R′ wherein R isalkylene and R′ is alkynyl as defined herein.

“Antagonist” refers to a compound that diminishes or prevents the actionof another compound or receptor site.

“Aryl” means a monovalent cyclic aromatic hydrocarbon moiety consistingof a mono-, bi- or tricyclic aromatic ring. The aryl group can beoptionally substituted as defined herein. Examples of aryl moietiesinclude, but are not limited to, optionally substituted phenyl,naphthyl, phenanthryl, fluorenyl, indenyl, pentalenyl, azulenyl,oxydiphenyl, biphenyl, methylenediphenyl, aminodiphenyl,diphenylsulfidyl, diphenylsulfonyl, diphenylisopropylidenyl,benzodioxanyl, benzofuranyl, benzodioxylyl, benzopyranyl, benzoxazinyl,benzoxazinonyl, benzopiperadinyl, benzopiperazinyl, benzopyrrolidinyl,benzomorpholinyl, methylenedioxyphenyl, ethylenedioxyphenyl, and thelike, including partially hydrogenated derivatives thereof.

“Arylalkyl” and “Aralkyl”, which may be used interchangeably, mean aradical-R^(a)R^(b) where R^(a) is an alkylene group and R^(b) is an arylgroup as defined herein; e.g., phenylalkyls such as benzyl, phenylethyl,3-(3-chlorophenyl)-2-methylpentyl, and the like are examples ofarylalkyl.

“Arylalkyl” means a group of the formula —R—R′ wherein R is alkylene andR′ is aryl as defined herein.

“Arylsulfonyl means a group of the formula —SO₂—R wherein R is aryl asdefined herein.

“Aryloxy” means a group of the formula —O—R wherein R is aryl as definedherein.

“Aralkyloxy” means a group of the formula —O—R—R″ wherein R is alkyleneand R′ is aryl as defined herein.

“Cyanoalkyl” ″ means a moiety of the formula —R′—R″, where R′ isalkylene as defined herein and R″ is cyano or nitrile.

“Cycloalkyl” means a monovalent saturated carbocyclic moiety consistingof mono- or bicyclic rings. Cycloalkyl can optionally be substitutedwith one or more substituents, wherein each substituent is independentlyhydroxy, alkyl, alkoxy, halo, haloalkyl, amino, monoalkylamino, ordialkylamino, unless otherwise specifically indicated. Examples ofcycloalkyl moieties include, but are not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like,including partially unsaturated derivatives thereof.

“Cycloalkylalkyl” means a moiety of the formula —R′—R″, where R′ isalkylene and R″ is cycloalkyl as defined herein.

“Heteroalkyl” means an alkyl radical as defined herein wherein one, twoor three hydrogen atoms have been replaced with a substituentindependently selected from the group consisting of —OR^(a),—NR^(b)R^(c), and —S(O)_(n)R^(d) (where n is an integer from 0 to 2),with the understanding that the point of attachment of the heteroalkylradical is through a carbon atom, wherein R^(a) is hydrogen, acyl,alkyl, cycloalkyl, or cycloalkylalkyl; R^(b) and R^(c) are independentlyof each other hydrogen, acyl, alkyl, cycloalkyl, or cycloalkylalkyl; andwhen n is 0, R^(d) is hydrogen, alkyl, cycloalkyl, or cycloalkylalkyl,and when n is 1 or 2, R^(d) is alkyl, cycloalkyl, cycloalkylalkyl,amino, acylamino, monoalkylamino, or dialkylamino. Representativeexamples include, but are not limited to, 2-hydroxyethyl,3-hydroxypropyl, 2-hydroxy-1-hydroxymethylethyl, 2,3-dihydroxypropyl,1-hydroxymethylethyl, 3-hydroxybutyl, 2,3-dihydroxybutyl,2-hydroxy-1-methylpropyl, 2-aminoethyl, 3-aminopropyl,2-methylsulfonylethyl, aminosulfonylmethyl, aminosulfonylethyl,aminosulfonylpropyl, methylaminosulfonylmethyl,methylaminosulfonylethyl, methylaminosulfonylpropyl, and the like.

“Heteroaryl” means a monocyclic or bicyclic radical of 5 to 12 ringatoms having at least one aromatic ring containing one, two, or threering heteroatoms selected from N, O, or S, the remaining ring atomsbeing C, with the understanding that the attachment point of theheteroaryl radical will be on an aromatic ring. The heteroaryl ring maybe optionally substituted as defined herein. Examples of heteroarylmoieties include, but are not limited to, optionally substitutedimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl,thiadiazolyl, pyrazinyl, thienyl, benzothienyl, thiophenyl, furanyl,pyranyl, pyridyl, pyrrolyl, pyrazolyl, pyrimidyl, quinolinyl,isoquinolinyl, benzofuryl, benzothiophenyl, benzothiopyranyl,benzimidazolyl, benzooxazolyl, benzooxadiazolyl, benzothiazolyl,benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, triazolyl,triazinyl, quinoxalinyl, purinyl, quinazolinyl, quinolizinyl,naphthyridinyl, pteridinyl, carbazolyl, azepinyl, diazepinyl, acridinyland the like, including partially hydrogenated derivatives thereof.

Heteroarylalkyl” or “heteroaralkyl” means a group of the formula —R—R′wherein R is alkylene and R′ is heteroaryl as defined herein.

“Heteroarylsulfonyl means a group of the formula —SO₂—R wherein R isheteroaryl as defined herein.

“Heteroaryloxy” means a group of the formula —O—R wherein R isheteroaryl as defined herein.

“Heteroaralkyloxy” means a group of the formula —O—R—R″ wherein R isalkylene and R′ is heteroaryl as defined herein.

The terms “halo”, “halogen” and “halide”, which may be usedinterchangeably, refer to a substituent fluoro, chloro, bromo, or iodo.

“Haloalkyl” means alkyl as defined herein in which one or more hydrogenhas been replaced with same or different halogen. Exemplary haloalkylsinclude —CH₂Cl, —CH₂CF₃, —CH₂CCl₃, perfluoroalkyl (e.g., —CF₃), and thelike.

“Haloalkoxy” means a moiety of the formula —OR, wherein R is a haloalkylmoiety as defined herein. An exemplary haloalkoxy is difluoromethoxy.

“Heterocycloamino” means a saturated ring wherein at least one ring atomis N, NH or N-alkyl and the remaining ring atoms form an alkylene group.

“Heterocyclyl” means a monovalent saturated moiety, consisting of one tothree rings, incorporating one, two, or three or four heteroatoms(chosen from nitrogen, oxygen or sulfur). The heterocyclyl ring may beoptionally substituted as defined herein. Examples of heterocyclylmoieties include, but are not limited to, optionally substitutedpiperidinyl, piperazinyl, homopiperazinyl, azepinyl, pyrrolidinyl,pyrazolidinyl, imidazolinyl, imidazolidinyl, pyridinyl, pyridazinyl,pyrimidinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl,isothiazolidinyl, quinuclidinyl, quinolinyl, isoquinolinyl,benzimidazolyl, thiadiazolylidinyl, benzothiazolidinyl,benzoazolylidinyl, dihydrofuryl, tetrahydrofuryl, dihydropyranyl,tetrahydropyranyl, thiamorpholinyl, thiamorpholinylsulfoxide,thiamorpholinylsulfone, dihydroquinolinyl, dihydrisoquinolinyl,tetrahydroquinolinyl, tetrahydrisoquinolinyl, and the like.

“Heterocyclylalkyl” means a moiety of the formula —R—R′ wherein R isalkylene and R′ is heterocyclyl as defined herein.

“Heterocyclyloxy” means a moiety of the formula —OR wherein R isheterocyclyl as defined herein.

“Heterocyclylalkoxy” means a moiety of the formula —OR—R′ wherein R isalkylene and R′ is heterocyclyl as defined herein.

“Hydroxyalkoxy” means a moiety of the formula —OR wherein R ishydroxyalkyl as defined herein.

“Hydroxyalkylamino” means a moiety of the formula —NR—R′ wherein R ishydrogen or alkyl and R′ is hydroxyalkyl as defined herein.

“Hydroxyalkylaminoalkyl” means a moiety of the formula —R—NR′—R″ whereinR is alkylene, R′ is hydrogen or alkyl, and R″ is hydroxyalkyl asdefined herein.

“Hydroxycarbonylalkyl” or “carboxyalkyl” means a group of the formula—R—(CO)—OH where R is alkylene as defined herein.

“Hydroxyalkyloxycarbonylalkyl” or “hydroxyalkoxycarbonylalkyl” means agroup of the formula —R—C(O)—O—R—OH wherein each R is alkylene and maybe the same or different.

“Hydroxyalkyl” means an alkyl moiety as defined herein, substituted withone or more, preferably one, two or three hydroxy groups, provided thatthe same carbon atom does not carry more than one hydroxy group.Representative examples include, but are not limited to, hydroxymethyl,2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl,1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl,4-hydroxybutyl, 2,3-dihydroxypropyl, 2-hydroxy-1-hydroxymethylethyl,2,3-dihydroxybutyl, 3,4-dihydroxybutyl and2-(hydroxymethyl)-3-hydroxypropyl

“Hydroxycycloalkyl” means a cycloalkyl moiety as defined herein whereinone, two or three hydrogen atoms in the cycloalkyl radical have beenreplaced with a hydroxy substituent. Representative examples include,but are not limited to, 2-, 3-, or 4-hydroxycyclohexyl, and the like.

“Urea” or “ureido” means a group of the formula —NR′—C(O)—NR″R′″ whereinR′, R″ and R′″ each independently is hydrogen or alkyl.

“Carbamate” means a group of the formula —O—C(O)—NR′R″ wherein R′ and R″each independently is hydrogen or alkyl.

“Carboxy” means a group of the formula —O—C(O)—OH.

“Sulfonamido” means a group of the formula —SO₂—NR′R″ wherein R′, R″ andR′″ each independently is hydrogen or alkyl.

Optionally substituted”, when used in association with “aryl”, phenyl”,“heteroaryl” “cycloalkyl” or “heterocyclyl”, means an aryl, phenyl,heteroaryl, cyclohexyl or heterocyclyl which is optionally substitutedindependently with one to four substituents, preferably one or twosubstituents selected from alkyl, cycloalkyl, cycloalkylalkyl,heteroalkyl, hydroxyalkyl, halo, nitro, cyano, hydroxy, alkoxy, amino,acylamino, mono-alkylamino, di-alkylamino, haloalkyl, haloalkoxy,heteroalkyl, —COR (where R is hydrogen, alkyl, phenyl or phenylalkyl),—(CR′R″)_(n)—COOR (where n is an integer from 0 to 5, R′ and R″ areindependently hydrogen or alkyl, and R is hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, phenyl or phenylalkyl), or —CR′R″)_(n)—CONR^(a)R^(b)(where n is an integer from 0 to 5, R′ and R″ are independently hydrogenor alkyl, and R^(a) and R^(b) are, independently of each other,hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl).

“Leaving group” means the group with the meaning conventionallyassociated with it in synthetic organic chemistry, i.e., an atom orgroup displaceable under substitution reaction conditions. Examples ofleaving groups include, but are not limited to, halogen, alkane- orarylenesulfonyloxy, such as methanesulfonyloxy, ethanesulfonyloxy,thiomethyl, benzenesulfonyloxy, tosyloxy, and thienyloxy,dihalophosphinoyloxy, optionally substituted benzyloxy, isopropyloxy,acyloxy, and the like.

“Modulator” means a molecule that interacts with a target. Theinteractions include, but are not limited to, agonist, antagonist, andthe like, as defined herein.

“Optional” or “optionally” means that the subsequently described eventor circumstance may but need not occur, and that the descriptionincludes instances where the event or circumstance occurs and instancesin which it does not.

“Disease” and “Disease state” means any disease, condition, symptom,disorder or indication.

“Inert organic solvent” or “inert solvent” means the solvent is inertunder the conditions of the reaction being described in conjunctiontherewith, including for example, benzene, toluene, acetonitrile,tetrahydrofuran, N,N-dimethylformamide, chloroform, methylene chlorideor dichloromethane, dichloroethane, diethyl ether, ethyl acetate,acetone, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol,tert-butanol, dioxane, pyridine, and the like. Unless specified to thecontrary, the solvents used in the reactions of the present inventionare inert solvents.

“Pharmaceutically acceptable” means that which is useful in preparing apharmaceutical composition that is generally safe, non-toxic, andneither biologically nor otherwise undesirable and includes that whichis acceptable for veterinary as well as human pharmaceutical use.

“Pharmaceutically acceptable salts” of a compound means salts that arepharmaceutically acceptable, as defined herein, and that possess thedesired pharmacological activity of the parent compound. Such saltsinclude:

acid addition salts formed with inorganic acids such as hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, andthe like; or formed with organic acids such as acetic acid,benzenesulfonic acid, benzoic, camphorsulfonic acid, citric acid,ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid,glutamic acid, glycolic acid, hydroxynaphtoic acid,2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid,malonic acid, mandelic acid, methanesulfonic acid, muconic acid,2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinicacid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, andthe like; or

salts formed when an acidic proton present in the parent compound eitheris replaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic or inorganicbase. Acceptable organic bases include diethanolamine, ethanolamine,N-methylglucamine, triethanolamine, tromethamine, and the like.Acceptable inorganic bases include aluminum hydroxide, calciumhydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.

The preferred pharmaceutically acceptable salts are the salts formedfrom acetic acid, hydrochloric acid, sulphuric acid, methanesulfonicacid, maleic acid, phosphoric acid, tartaric acid, citric acid, sodium,potassium, calcium, zinc, and magnesium.

It should be understood that all references to pharmaceuticallyacceptable salts include solvent addition forms (solvates) or crystalforms (polymorphs) as defined herein, of the same acid addition salt.

“Protective group” or “protecting group” means the group whichselectively blocks one reactive site in a multifunctional compound suchthat a chemical reaction can be carried out selectively at anotherunprotected reactive site in the meaning conventionally associated withit in synthetic chemistry. Certain processes of this invention rely uponthe protective groups to block reactive nitrogen and/or oxygen atomspresent in the reactants. For example, the terms “amino-protectinggroup” and “nitrogen protecting group” are used interchangeably hereinand refer to those organic groups intended to protect the nitrogen atomagainst undesirable reactions during synthetic procedures. Exemplarynitrogen protecting groups include, but are not limited to,trifluoroacetyl, acetamido, benzyl (Bn), benzyloxycarbonyl(carbobenzyloxy, CBZ), p-methoxybenzyloxycarbonyl,p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl (BOC), and the like. Theartisan in the art will know how to chose a group for the ease ofremoval and for the ability to withstand the following reactions.

“Solvates” means solvent additions forms that contain eitherstoichiometric or non stoichiometric amounts of solvent. Some compoundshave a tendency to trap a fixed molar ratio of solvent molecules in thecrystalline solid state, thus forming a solvate. If the solvent is waterthe solvate formed is a hydrate, when the solvent is alcohol, thesolvate formed is an alcoholate. Hydrates are formed by the combinationof one or more molecules of water with one of the substances in whichthe water retains its molecular state as H₂O, such combination beingable to form one or more hydrate.

“Subject” means mammals and non-mammals. Mammals means any member of themammalia class including, but not limited to, humans; non-human primatessuch as chimpanzees and other apes and monkey species; farm animals suchas cattle, horses, sheep, goats, and swine; domestic animals such asrabbits, dogs, and cats; laboratory animals including rodents, such asrats, mice, and guinea pigs; and the like. Examples of non-mammalsinclude, but are not limited to, birds, and the like. The term “subject”does not denote a particular age or sex.

“Disorders of the urinary tract” or “uropathy” used interchangeably with“symptoms of the urinary tract” means the pathologic changes in theurinary tract. Examples of urinary tract disorders include, but are notlimited to, incontinence, benign prostatic hypertrophy (BPH),prostatitis, detrusor hyperreflexia, outlet obstruction, urinaryfrequency, nocturia, urinary urgency, overactive bladder, pelvichypersensitivity, urge incontinence, urethritis, prostatodynia,cystitis, idiophatic bladder hypersensitivity, and the like.

“Disease states associated with the urinary tract” or “urinary tractdisease states” or “uropathy” used interchangeably with “symptoms of theurinary tract” mean the pathologic changes in the urinary tract, ordysfunction of urinary bladder smooth muscle or its innervation causingdisordered urinary storage or voiding. Symptoms of the urinary tractinclude, but are not limited to, overactive bladder (also known asdetrusor hyperactivity), outlet obstruction, outlet insufficiency, andpelvic hypersensitivity.

“Overactive bladder” or “detrusor hyperactivity” includes, but is notlimited to, the changes symptomatically manifested as urgency,frequency, altered bladder capacity, incontinence, micturitionthreshold, unstable bladder contractions, sphincteric spasticity,detrusor hyperreflexia (neurogenic bladder), detrusor instability, andthe like.

“Outlet obstruction” includes, but is not limited to, benign prostatichypertrophy (BPH), urethral stricture disease, tumors, low flow rates,difficulty in initiating urination, urgency, suprapubic pain, and thelike.

“Outlet insufficiency” includes, but is not limited to, urethralhypermobility, intrinsic sphincteric deficiency, mixed incontinence,stress incontinence, and the like.

“Pelvic Hypersensitivity” includes, but is not limited to, pelvic pain,interstitial (cell) cystitis, prostatodynia, prostatitis, vulvadynia,urethritis, orchidalgia, overactive bladder, and the like.

“Respiratory disorder” refers to, without limitation, chronicobstructive pulmonary disease (COPD), asthma, bronchospasm, and thelike.

“Gastrointestinal disorder” (“GI disorder”) refers to, withoutlimitation, Irritable Bowel Syndrome (IBS), Inflammatory Bowel Disease(IBD), biliary colic and other biliary disorders, renal colic,diarrhea-dominant IBS, pain associated with GI distension, and the like.

“Therapeutically effective amount” means an amount of a compound that,when administered to a subject for treating a disease state, issufficient to effect such treatment for the disease state. The“therapeutically effective amount” will vary depending on the compound,disease state being treated, the severity or the disease treated, theage and relative health of the subject, the route and form ofadministration, the judgment of the attending medical or veterinarypractitioner, and other factors.

The terms “those defined above” and “those defined herein” whenreferring to a variable incorporates by reference the broad definitionof the variable as well as preferred, more preferred and most preferreddefinitions, if any.

“Treating” or “treatment” of a disease state includes:

-   -   (i) preventing the disease state, i.e. causing the clinical        symptoms of the disease state not to develop in a subject that        may be exposed to or predisposed to the disease state, but does        not yet experience or display symptoms of the disease state.    -   (ii) inhibiting the disease state, i.e., arresting the        development of the disease state or its clinical symptoms, or    -   (iii) relieving the disease state, i.e., causing temporary or        permanent regression of the disease state or its clinical        symptoms.

The terms “treating”, “contacting” and “reacting” when referring to achemical reaction means adding or mixing two or more reagents underappropriate conditions to produce the indicated and/or the desiredproduct. It should be appreciated that the reaction which produces theindicated and/or the desired product may not necessarily result directlyfrom the combination of two reagents which were initially added, i.e.,there may be one or more intermediates which are produced in the mixture

which ultimately leads to the formation of the indicated and/or thedesired product.

Nomenclature and Structures

In general, the nomenclature used in this application is based onAUTONOM™ v.4.0, a Beilstein Institute computerized system for thegeneration of IUPAC systematic nomenclature. Chemical structures shownherein were prepared using ISIS® version 2.2. Any open valency appearingon a carbon, oxygen or nitrogen atom in the structures herein indicatesthe presence of a hydrogen atom. Where a chiral center exists in astructure but no specific stereochemistry is shown for the chiralcenter, both enantiomers associated with the chiral structure areencompassed by the structure.

All patents and publications identified herein are incorporated hereinby reference in their entirety.

Compounds of the Invention

The invention provides compounds of the formula (I):

or pharmaceutically acceptable salts thereof,wherein:X is:

-   -   —CH₂—;    -   —O—;    -   —S(O)_(n)—;    -   or —NR^(c)—    -   wherein        -   n is from 0 to 2 and        -   R^(c) is hydrogen or alkyl;            D is an optional oxygen;            R¹ is:    -   alkyl;    -   alkenyl;    -   cycloalkyl;    -   cycloalkenyl;    -   halo;    -   haloalkyl; or    -   hydroxyalkyl;        R², R³, and R⁴ each independently is:    -   hydrogen;    -   alkyl;    -   alkenyl;    -   amino;    -   halo;    -   amido;    -   haloalkyl;    -   alkoxy;    -   hydroxy;    -   haloalkoxy;    -   nitro; amino;    -   hydroxyalkyl;    -   alkoxyalkyl;    -   hydroxyalkoxy;    -   alkynylalkoxy;    -   alkylsulfonyl;    -   arylsulfonyl;    -   cyano;    -   aryl;    -   heteroaryl;    -   heterocyclyl;    -   heterocyclylalkoxy;    -   aryloxy;    -   heteroaryloxy;    -   aralkyloxy;    -   heteroaralkyloxy;    -   optionally substituted phenoxy;    -   —C≡C—R^(a);    -   —(CH₂)_(m)-(Z)_(n)-(CO)—R^(b);    -   —(CH₂)_(m)-(Z)_(n)-SO₂—(NR^(c))_(n)—R^(b)    -   wherein        -   m and n each independently is 0 or 1,        -   Z is O or NR^(c),        -   R^(a) is hydrogen; alkyl; aryl; aralkyl; heteroaryl;            heteroaralkyl; hydroxyalkyl; alkoxyalkyl;            alkylsulfonylalkyl; aminoalkyl; cyanoalkyl; alkylsilyl,            cycloalkyl, cycloalkylalkyl; heterocycl; and            heterocyclylalkyl;        -   R^(b) is hydrogen, alkyl, hydroxy, alkoxy, amino,            hydroxyalkyl or alkoxyalkyl, and each R^(c) is independently            hydrogen or alkyl;    -   or R² and R³ together with the atoms to which they are attached        may form a five or six-membered ring that optionally includes        one or two heteroatoms selected from O, S and        N;        R⁵ is:    -   hydrogen;    -   alkyl;    -   aryl;    -   aralkyl;    -   heteroaryl;    -   heteroaralkyl;    -   hydroxyalkyl;    -   alkoxyalkyl;    -   alkylsulfonylalkyl;    -   aminoalkyl;    -   cyanoalkyl;    -   alkylsilyl,    -   cycloalkyl,    -   cycloalkylalkyl;    -   heterocycl; or    -   heterocyclylalkyl;        R⁶ is:    -   hydrogen;    -   alkyl;    -   halo;    -   haloalkyl;    -   amino; or    -   alkoxy; and        R⁷ and R⁸ each independently is:    -   hydrogen;    -   alkyl;    -   alkoxyalkyl;    -   aminoalkyl;    -   aminosulfonyl;    -   cycloalkyl;    -   cycloalkylalkyl;    -   haloalkyl;    -   haloalkoxy;    -   hydroxyalkyl;    -   alkoxyalkyl;    -   alkylsulfonyl;    -   alkylsulfonylalkyl;    -   aminocarbonyloxyalkyl;    -   hydroxycarbonylalkyl;    -   hydroxyalkyloxycarbonylalkyl;    -   aryl;    -   aralkyl;    -   arylsulfonyl;    -   heteroaryl;    -   heteroarylalkyl;    -   heteroarylsulfonyl;    -   heterocyclyl; or    -   heterocyclylalkyl.

In certain embodiments of the invention, R⁴ and R⁶ are hydrogen.

In certain embodiments of the invention, R² is hydrogen.

In certain embodiments of the invention, D is absent.

In certain embodiments of formula I, X is —O— or —CH₂—.

In certain embodiments of formula I, X is —O—.

In certain embodiments of formula I, R¹ is isopropyl, iodo or ethynyl.Preferably R¹ is isopropyl.

In certain embodiments of formula I, R² and R⁴ are hydrogen.

In certain embodiments of formula I, R³ is hydrogen, alkoxy, hydroxy, orhalo. Preferably R³ is alkoxy.

In certain embodiments of formula I, R⁵ is hydrogen, alkyl, phenyl,pyridyl, methoxymethyl, hydroxyethyl, cyanoethyl, thienyl, imidazolyl,hydroxypropyl, methylamino, hydroxymethyl, trimethylsilyl orcyclopropyl. Preferably R⁵ is hydrogen.

In certain embodiments of formula I, R⁷ and R⁸ each independently ishydrogen, alkyl, hydroxyalkyl, aminoalkyl, heterocyclyl orheterocyclylalkyl.

In certain embodiments of formula I, one of R⁷ and R⁸ is hydrogen andthe other is alkyl, hydroxyalkyl, aminoalkyl, heterocyclyl orheterocyclylalkyl.

In certain embodiments of formula I, X is —O—, R¹ is isopropyl or iodo,R² and R⁴ are hydrogen, R³ is alkoxy, hydroxy, or halo, R⁵ is hydrogen,alkyl, phenyl, pyridyl, methoxymethyl, hydroxyethyl, cyanoethyl,thienyl, imidazolyl, hydroxypropyl, methylamino, hydroxymethyl,trimethylsilyl or cyclopropyl, and one of R⁷ and R⁸ is hydrogen and theother is alkyl, hydroxyalkyl, aminoalkyl, heterocyclyl orheterocyclylalkyl.

In embodiments of the invention wherein R⁷ or R⁸ is hydroxyalkyl,preferred hydroxyalkyl include hydroxyethyl, 2-hydroxypropyl,3-hydroxy-2-methyl-ethyl, 2-hydroxy-1-(hydroxymethyl)-ethyl and3-hydroxypropyl.

In certain embodiments of formula I, X is —O—, R¹ is isopropyl, R² andR⁴ are hydrogen, R³ is hydrogen, alkoxy or halo, R⁵ is hydrogen, and R⁷and R⁸ each independently is hydrogen, or hydroxyalkyl.

In certain embodiments of formula I, X is —O—, R¹ is isopropyl, iodo orethynyl, R² and R⁴ are hydrogen, R³ is hydrogen, alkoxy, hydroxy, orhalo, R⁵ is hydrogen, alkyl, phenyl, pyridyl, methoxymethyl,hydroxyethyl, cyanoethyl, thienyl, imidazolyl, hydroxypropyl,methylamino, hydroxymethyl, trimethylsilyl or cyclopropyl, R⁷ ishydrogen, and R⁸ is hydrogen, alkyl, hydroxyalkyl, aminoalkyl,heterocyclyl or heterocyclylalkyl.

In certain embodiments of formula I, X is —O—, R¹ is isopropyl, iodo orethynyl, R² and R⁴ are hydrogen, R³ is hydrogen, alkoxy, hydroxy, orhalo, R⁵ is hydrogen, R⁷ is hydrogen, and R⁸ is hydrogen, alkyl,hydroxyalkyl, aminoalkyl, heterocyclyl or heterocyclylalkyl.

In certain embodiments of formula I, X is —O—, R¹ is isopropyl, iodo orethynyl, R² and R⁴ are hydrogen, R³ is hydrogen, alkoxy, hydroxy, orhalo, R⁵ is hydrogen, R⁸ is hydrogen, and R⁸ is hydrogen, alkyl,hydroxyalkyl, aminoalkyl, heterocyclyl or heterocyclylalkyl.

In certain embodiments of formula I, X is —O—, R¹ is isopropyl, R² andR⁴ are hydrogen, R³ is alkoxy or halo, R⁵ is hydrogen, R⁷ is hydrogen,and R⁸ is hydrogen or hydroxyalkyl.

In certain embodiments of formula I, X is —O—, R¹ is isopropyl, R² andR⁴ are hydrogen, R³ is alkoxy or halo, R⁵ is hydrogen, R⁸ is hydrogen,and R⁷ is hydrogen or hydroxyalkyl.

In embodiments of the invention where R⁷ or R⁸ is hydroxyalkyl,preferred hydroxyalkyl include hydroxyethyl, 2-hydroxypropyl,2-hydroxy-1-methyl-ethyl, 2-hydroxy-1-hydroxymethyl)-ethyl and3-hydroxypropyl.

In embodiments of the invention where R⁷ or R⁸ is heterocyclyl,preferred heterocyclyl include tetrahydropyranyl and piperidinyl. Incertain embodiments the heterocyclyl may be tetrahydropyran-4-yl, orpiperidin-4-yl optionally substituted at the one position withmethanesulfonyl, alkyl or acetyl.

In embodiments of the invention where R⁷ or R⁸ is heterocyclylalkyl,preferred heterocyclylalkyl include morpholinylalkyl, piperidinylalkyland piperazinylalkyl. In certain embodiments the heterocyclylalkyl maybe morpholin-4-yl-ethyl, or piperidin-1-yl-ethyl.

In embodiments of the invention where R⁵ is heteroaryl, preferredheteroaryl include pyridinyl, thienyl and imidazolyl. In certainembodiments the heteroaryl may be pyridin-2-yl, pyridin-3-yl,pyridin-4-yl, thien-3-yl and 1-methyl-imidazol-2-yl.

In certain embodiments of the invention, the subject compounds are morespecifically of formula II:

wherein X, R¹, R³, R⁵, R⁷ and R⁸ are as defined herein.

In certain embodiments of either of formula I or II, X is —O— or —CH₂—.More preferably X is —O—.

In certain embodiments of formula II, R¹ is isopropyl, iodo or ethynyl.Preferably R¹ is isopropyl.

In certain embodiments of formula II, R³ is hydrogen, alkoxy, hydroxy,or halo.

In certain embodiments of formula II, R⁵ is hydrogen, alkyl, phenyl,pyridyl, methoxymethyl, hydroxyethyl, cyanoethyl, thienyl, imidazolyl,hydroxypropyl, methylamino, hydroxymethyl, trimethylsilyl orcyclopropyl. Preferably R⁵ is hydrogen.

In certain embodiments of formula I, R⁷ and R⁸ each independently ishydrogen, alkyl, hydroxyalkyl, aminoalkyl, heterocyclyl orheterocyclylalkyl.

In certain embodiments of formula II, X is —O—, R¹ is isopropyl or iodo,R³ is hydrogen, alkoxy, hydroxy, or halo, R⁵ is hydrogen, alkyl, phenyl,pyridyl, methoxymethyl, hydroxyethyl, cyanoethyl, thienyl, imidazolyl,hydroxypropyl, methylamino, hydroxymethyl, trimethylsilyl orcyclopropyl, and R⁷ and R⁸ each independently is hydrogen, alkyl,hydroxyalkyl, aminoalkyl, heterocyclyl or heterocyclylalkyl.

In certain embodiments of formula II, X is —O—, R¹ is isopropyl, iodo orethynyl, R³ is hydrogen, alkoxy, hydroxy, or halo, R⁵ is hydrogen, andR⁷ and R⁸ each independently is hydrogen, or hydroxyalkyl.

In certain embodiments of formula II, X is —O—, R¹ is isopropyl, iodo orethynyl, R³ is hydrogen, alkoxy, hydroxy, or halo, R⁵ is hydrogen,alkyl, phenyl, pyridyl, methoxymethyl, hydroxyethyl, cyanoethyl,thienyl, imidazolyl, hydroxypropyl, methylamino, hydroxymethyl,trimethylsilyl or cyclopropyl, R⁷ is hydrogen, and R⁸ is hydrogen,alkyl, hydroxyalkyl, aminoalkyl, heterocyclyl or heterocyclylalkyl.

In certain embodiments of formula II, X is —O—, R¹ is isopropyl, iodo orethynyl, R³ is hydrogen, alkoxy or halo, R⁵ is hydrogen, R⁷ is hydrogen,and R⁸ is hydrogen, alkyl, hydroxyalkyl, aminoalkyl, heterocyclyl orheterocyclylalkyl.

In certain embodiments of formula II, X is —O—, R¹ is isopropyl, iodo orethynyl, R³ is hydrogen, alkoxy or halo, R⁵ is hydrogen, R⁸ is hydrogen,and R⁷ is hydrogen, alkyl, hydroxyalkyl, aminoalkyl, heterocyclyl orheterocyclylalkyl.

In certain embodiments of formula II, X is —O—, R¹ is isopropyl, R³ isalkoxy or halo, R⁵ is hydrogen, R⁷ is hydrogen, and R⁸ is hydrogen orhydroxyalkyl.

In certain embodiments of formula II, X is —O—, R¹ is isopropyl, R³ isalkoxy or halo, R⁵ is hydrogen, R⁸ is hydrogen, and R⁷ is hydrogen orhydroxyalkyl.

In certain embodiments of the invention, the subject compounds are morespecifically of formula III:

wherein R¹, R³, R⁵, R⁷ and R⁸ are as defined herein.

In certain embodiments of any of formulas I, II or III, R¹ may be ethyl,isopropyl, iodo, ethynyl or cyclopropyl. In certain of such embodimentsR¹ may be isopropyl, iodo or ethynyl. Preferably R¹ is isopropyl.

In certain embodiments of any of formulas I, II or III, R⁷ and R⁸ arehydrogen.

In certain embodiments of any of formulas I, II or III, one of R⁷ and R⁸is hydrogen and the other is hydrogen, alkyl, hydroxyalkyl or haloalkyl.

In certain embodiments of any of formulas I, II or III, one of R⁷ and R⁸is hydrogen and the other is hydrogen or hydroxyalkyl.

In certain embodiments of any of formulas I, II or III, one of R⁷ and R⁸is hydrogen and the other is hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, haloalkyl, hydroxyalky; or alkoxyalkyl.

In certain embodiments of any of formulas I, II or III, R³ may behydrogen, alkyl, alkenyl, halo, haloalkyl, alkoxy, hydroxy, haloalkoxy,alkylsulfonyl, cyano or —C≡C—R^(a).

In certain embodiments of any of formulas I, II or III, R³ may behydrogen, halo, alkoxy, haloalkoxy, hydroxy, alkylsulfonyl, or—C≡C—R^(a).

In certain embodiments of any of formulas I, II or III, R³ may behydrogen; halo; alkoxy; haloalkoxy; alkylsulfonyl; or hydroxy.

In certain embodiments of any of formulas I, II or III, R³ may behydrogen, halo, alkoxy, haloalkoxy or hydroxy.

In certain embodiments of any of formulas I, II or III, R³ may behydrogen, halo, alkoxy or hydroxy.

In certain embodiments of any of formulas I, II or III, R³ may behydrogen, alkoxy or hydroxy.

In certain embodiments of any of formulas I, II or III, R³ may be alkoxyor hydroxy.

In certain embodiments of any of formulas I, II or III, R⁵ may behydrogen, alkyl; optionally substituted phenyl, optionally substitutedpyridinyl, optionally substituted thienyl, optionally substitutedimidazolyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cyanoalkyl,alkylsilyl or cycloalkyl.

In certain embodiments of any of formulas I, II or III, R⁵ may behydrogen or alkyl.

In certain embodiments of any of formulas I, II or III, R⁵ may behydrogen or methyl.

In certain embodiments of any of formulas I, II or III, R⁵ may beheteroaryl selected from pyridinyl, pyrimdinyl, thienyl, furanyl,imidazolyl, pyrazolyl and pyrrolyl.

In certain embodiments of any of formulas I, II or III, R⁵ may behydrogen, methyl, ethyl, propyl, phenyl, methoxymethyl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, 2-hydroxyethyl, 3-hydroxypropyl,hydroxymenthyl, methylaminomethyl, 2-cyanoethyl, thien-3-yl,1-methylimidazol-5-yl, trimethylsilyl or cyclopropyl.

In certain embodiments of any of formulas I, II or III, R¹ is isopropyl,iodo, or ethynyl and R⁷ and R⁸ are hydrogen.

In certain embodiments of any of formulas I, II or III, R¹ is isopropyl,iodo, or ethynyl, R⁷ and R⁸ are hydrogen, and R³ is hydrogen, alkoxy orhydroxy.

In certain embodiments of any of formulas I, II or III, R¹ is isopropyl,iodo, or ethynyl, R⁷ and R⁸ are hydrogen, R³ is hydrogen, alkoxy orhydroxy, and R⁵ is hydrogen or methyl.

In certain embodiments of any of formulas I, II or III, R¹ is isopropyl,iodo, or ethynyl, one of R⁷ and R⁸ is hydrogen and the other is hydrogenor hydroxyalkyl, R³ is hydrogen, alkoxy or hydroxy, and R⁵ is hydrogen.

In certain embodiments of the invention, the subject compounds are morespecifically of formula IV:

wherein R³, R⁵, R⁷ and R⁸ are as defined herein.

In certain embodiments of formula IV, R⁷ and R⁸ are hydrogen.

In certain embodiments of formula IV, one of R⁷ and R⁸ is hydrogen andthe other is alkyl, hydroxyalkyl or haloalkyl.

In certain embodiments of formula IV, one of R⁷ and R⁸ is hydrogen andthe other is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl,hydroxyalky; or alkoxyalkyl.

In certain embodiments of formula IV, R³ may be hydrogen, alkyl,alkenyl, halo, haloalkyl, alkoxy, hydroxy, haloalkoxy, alkylsulfonyl,cyano or —C≡C—R^(a).

In certain embodiments of formula IV, R³ may be hydrogen, halo, alkoxy,haloalkoxy, hydroxy, alkylsulfonyl, or —C≡C—R^(a).

In certain embodiments of formula IV, R³ may be hydrogen; halo; alkoxy;haloalkoxy; alkylsulfonyl; or hydroxy.

In certain embodiments of formula IV, R³ may be hydrogen, halo, alkoxy,haloalkoxy or hydroxy.

In certain embodiments of formula IV, R³ may be hydrogen, halo, alkoxyor hydroxy.

In certain embodiments of formula IV, R³ may be hydrogen, alkoxy orhydroxy.

In certain embodiments of formula IV, R³ may be alkoxy or hydroxy.

In certain embodiments of formula IV, R⁵ may be hydrogen, alkyl;optionally substituted phenyl, optionally substituted pyridinyl,optionally substituted thienyl, optionally substituted imidazolyl,hydroxyalkyl, alkoxyalkyl, aminoalkyl, cyanoalkyl, alkylsilyl orcycloalkyl.

In certain embodiments of formula IV, R⁵ may be hydrogen or alkyl.

In certain embodiments of formula IV, R⁵ may be hydrogen or methyl.

In certain embodiments of formula IV, R⁵ may be heteroaryl selected frompyridinyl, pyrimdinyl, thienyl, furanyl, imidazolyl, pyrazolyl andpyrrolyl.

In certain embodiments of formula IV, R⁵ may be hydrogen, methyl, ethyl,propyl, phenyl, methoxymethyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,2-hydroxyethyl, 3-hydroxypropyl, hydroxymenthyl, methylaminomethyl,2-cyanoethyl, thien-3-yl, 1-methylimidazol-5-yl, trimethylsilyl orcyclopropyl.

In certain embodiments of formula IV, R⁷ and R⁸ are hydrogen and R³ ishydrogen, alkoxy or hydroxy.

In certain embodiments of formula IV, R⁷ and R⁸ are hydrogen, R³ ishydrogen, alkoxy or hydroxy, and R⁵ is hydrogen or methyl.

In certain embodiments of formula IV, R³ is hydrogen, halo, alkoxy orhydroxy, R⁵ is hydrogen, one of R⁷ and R⁸ is hydrogen, and the other ishydrogen or hydroxyalkyl.

In certain embodiments of formula IV, R³ is hydrogen, halo, alkoxy orhydroxy, R⁵ is hydrogen, R⁷ is hydrogen, and R⁸ is hydrogen orhydroxyalkyl.

In certain embodiments of formula IV, R³ is hydrogen, halo, alkoxy orhydroxy, R⁵ is hydrogen, R⁸ is hydrogen, and R⁷ is hydrogen orhydroxyalkyl.

In certain embodiments of the invention, the subject compounds are morespecifically of formula V:

wherein R³ and R⁵ are as defined herein.

In certain embodiments of formula V, R³ may be hydrogen, alkyl, alkenyl,halo, haloalkyl, alkoxy, hydroxy, haloalkoxy, alkylsulfonyl, cyano or—C≡C—R^(a).

In certain embodiments of formula IV, R³ may be hydrogen, halo, alkoxy,haloalkoxy, hydroxy, alkylsulfonyl, or —C≡C—R^(a).

In certain embodiments of formula V, R³ may be hydrogen; halo; alkoxy;haloalkoxy; alkylsulfonyl; or hydroxy.

In certain embodiments of formula V, R³ may be hydrogen, halo, alkoxy,haloalkoxy or hydroxy.

In certain embodiments of formula V, R³ may be hydrogen, halo, alkoxy orhydroxy.

In certain embodiments of formula V, R³ may be hydrogen, alkoxy orhydroxy.

In certain embodiments of formula V, R³ may be alkoxy or hydroxy.

In certain embodiments of formula V, R⁵ may be hydrogen, alkyl;optionally substituted phenyl, optionally substituted pyridinyl,optionally substituted thienyl, optionally substituted imidazolyl,hydroxyalkyl, alkoxyalkyl, aminoalkyl, cyanoalkyl, alkylsilyl orcycloalkyl.

In certain embodiments of formula V, R⁵ may be hydrogen or alkyl.

In certain embodiments of formula V, R⁵ may be hydrogen or methyl.

In certain embodiments of formula V, R⁵ may be heteroaryl selected frompyridinyl, pyrimdinyl, thienyl, furanyl, imidazolyl, pyrazolyl andpyrrolyl.

In certain embodiments of formula V, R⁵ may be hydrogen, methyl, ethyl,propyl, phenyl, methoxymethyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,2-hydroxyethyl, 3-hydroxypropyl, hydroxymenthyl, methylaminomethyl,2-cyanoethyl, thien-3-yl, 1-methylimidazol-5-yl, trimethylsilyl orcyclopropyl.

In certain embodiments of formula V, R³ is hydrogen, alkoxy or hydroxy,and R⁵ is hydrogen or methyl.

In certain embodiments of the invention, the subject compounds are morespecifically of formula VI:

wherein

-   -   R⁹ is hydrogen or alkyl, and    -   X, R³, R⁵, R⁷ and R⁸ are as defined herein.

In another aspect of the invention, there are provided compounds of theformula VII:

or pharmaceutically acceptable salts thereof,wherein:X is:

-   -   —CH₂—;    -   —O—;    -   —S(O)_(n)—;    -   or —NR^(c)—    -   wherein        -   n is from 0 to 2 and        -   R^(c) is hydrogen or alkyl;            D is an optional oxygen;            R², R³, R⁴ and R¹⁰ each independently is:    -   hydrogen;    -   alkyl;    -   alkenyl;    -   amino;    -   halo;    -   amido;    -   haloalkyl;    -   alkoxy;    -   hydroxy;    -   haloalkoxy;    -   nitro; amino;    -   hydroxyalkyl;    -   alkoxyalkyl;    -   hydroxyalkoxy;    -   alkynylalkoxy;    -   alkylsulfonyl;    -   arylsulfonyl;    -   cyano;    -   aryl;    -   heteroaryl;    -   heterocyclyl;    -   heterocyclylalkoxy;    -   aryloxy;    -   heteroaryloxy;    -   aralkyloxy;    -   heteroaralkyloxy;    -   optionally substituted phenoxy;    -   —C≡C—R^(a);    -   —(CH₂)_(m)-(Z)_(n)-(CO)—R^(b);    -   —(CH₂)_(m)-(Z)_(n)-SO₂—(NR^(c))_(n)—R^(b)    -   wherein        -   m and n each independently is 0 or 1,        -   Z is O or NR^(c),        -   R^(a) is hydrogen; alkyl; aryl; aralkyl; heteroaryl;            heteroaralkyl; hydroxyalkyl; alkoxyalkyl;            alkylsulfonylalkyl; aminoalkyl; cyanoalkyl; alkylsilyl,            cycloalkyl, cycloalkylalkyl; heterocycl; and            heterocyclylalkyl;        -   R^(b) is hydrogen, alkyl, hydroxy, alkoxy, amino,            hydroxyalkyl or alkoxyalkyl, and        -   each R^(c) is independently hydrogen or alkyl;    -   or R² and R³ together with the atoms to which they are attached        may form a five or six-membered ring that optionally includes        one or two heteroatoms selected from O, S and        N;        R⁶ is:    -   hydrogen;    -   alkyl;    -   halo;    -   haloalkyl;    -   amino; or    -   alkoxy; and        R⁷ and R⁸ each independently is:    -   hydrogen;    -   alkyl;    -   cycloalkyl;    -   cycloalkylalkyl;    -   haloalkyl;    -   haloalkoxy;    -   hydroxyalky;    -   alkoxyalkyl;    -   alkylsulfonyl;    -   alkylsulfonylalkyl;    -   aminocarbonyloxyalkyl;    -   hydroxycarbonylalkyl;    -   hydroxyalkyloxycarbonylalkyl;    -   aryl;    -   aralkyl;    -   arylsulfonyl;    -   heteroaryl;    -   heteroarylalkyl;    -   heteroarylsulfonyl;    -   heterocyclyl; or    -   heterocyclylalkyl.

In certain embodiments of formula VII, D is absent

In certain embodiments of formula VII, R², R⁴ and R⁶ are hydrogen.

In certain embodiments of formula VII, X is —O— or —CH₂—, R², R⁴ and R⁶are hydrogen, R³ is alkoxy or hydroxy, R¹⁰ is iodo, alkoxy,alkylsulfonyl, or —C≡C—R^(a), and R⁷ and R⁸ are hydrogen. Preferably Xis —O— in such embodiments.

In certain embodiments of formula VII, the subject compounds are morespecifically of the formula VIII:

wherein R³, R⁷, R⁸, R⁹ and R¹⁰ are as defined herein.

In certain embodiments of either of formula VII of VIII, X is —O— or—CH₂—. More preferably X is —O—.

In certain embodiments of formula IX, the subject compounds are morespecifically of the formula IX:

wherein R³, R⁷, R⁸, R⁹ and R¹⁰ are as defined herein.

In certain embodiments of any of formulas VII, VIII and IX, R⁷ and R⁸may both be hydrogen.

In certain embodiments of any of formulas VII, VIII and IX, one of R⁷and R⁸ may is hydrogen and the other is alkyl, hydroxyalkyl orhaloalkyl.

In certain embodiments of any of formulas VII, VIII and IX, R³ and R¹⁰each independently may be hydrogen, alkyl, alkenyl, halo, haloalkyl,alkoxy, hydroxy, haloalkoxy, alkylsulfonyl, cyano or —C≡C—R^(a).

In certain embodiments of any of formulas VII, VIII and IX, R³ and R¹⁰each independently may be hydrogen, halo, alkoxy, haloalkoxy, hydroxy,alkylsulfonyl, or —C≡C—R^(a).

In certain embodiments of any of formulas VII, VIII and Ix, R³ and R¹⁰each independently may be halo; alkoxy; haloalkoxy; alkylsulfonyl;hydroxy or —C≡C—R^(a).

In certain embodiments of any of formulas VII, VIII and IX, R³ may behydrogen, halo, alkoxy, haloalkoxy or hydroxy, and R¹⁰ may be halo,alkylsulfonyl, or —C≡C—R^(a).

In certain embodiments of any of formulas VII, VIII and IX, R³ may bealkoxy or hydroxy, and R¹⁰ may be iodo, alkylsulfonyl, or —C≡C—R^(a).

In certain embodiments of any of formulas VII, VIII and IX, R³ is alkoxyor hydroxy, R¹⁰ is iodo, alkylsulfonyl, or —C≡C—R^(a)—, and R⁷ and R⁸are hydrogen.

In another aspect of the invention compounds of the formula (X) areprovided:

or pharmaceutically acceptable salts thereof,wherein:X is:

-   -   —CH₂—;    -   —O—;    -   —S(O)_(n)—;    -   or —NR^(c)—    -   wherein        -   n is from 0 to 2 and        -   R^(c) is hydrogen or alkyl;            D is an optional oxygen;            R¹ is:    -   alkyl;    -   alkenyl;    -   cycloalkyl;    -   cycloalkenyl;    -   halo;    -   haloalkyl; or    -   hydroxyalkyl;        R¹¹ is:    -   alkyl;    -   alkenyl;    -   amino;    -   halo;    -   amido;    -   haloalkyl;    -   alkoxy;    -   hydroxy;    -   haloalkoxy;    -   nitro; amino;    -   hydroxyalkyl;    -   alkoxyalkyl;    -   hydroxyalkoxy;    -   alkynylalkoxy;    -   alkylsulfonyl;    -   arylsulfonyl;    -   cyano;    -   aryl;    -   heteroaryl;    -   heterocyclyl;    -   heterocyclylalkoxy;    -   aryloxy;    -   heteroaryloxy;    -   aralkyloxy;    -   heteroaralkyloxy;    -   optionally substituted phenoxy;    -   —C≡C—R^(a);    -   —(CH₂)_(m)-(Z)_(n)-(CO)—R^(b);    -   —(CH₂)_(m)-(Z)_(n)-SO₂—(NR^(c))_(n)—R^(b)    -   wherein        -   m and n each independently is 0 or 1,        -   Z is O or NR^(c),        -   R^(a) is hydrogen; alkyl; aryl; aralkyl; heteroaryl;            heteroaralkyl; hydroxyalkyl; alkoxyalkyl;            alkylsulfonylalkyl; aminoalkyl; cyanoalkyl; alkylsilyl,            cycloalkyl, cycloalkylalkyl; heterocycl; and            heterocyclylalkyl;        -   R^(b) is hydrogen, alkyl, hydroxy, alkoxy, amino,            hydroxyalkyl or alkoxyalkyl, and        -   each R^(c) is independently hydrogen or alkyl;    -   or R² and R³ together with the atoms to which they are attached        may form a five or six-membered ring that optionally includes        one or two heteroatoms selected from O, S and        N;        R¹² is alkoxy or hydroxy; and        R⁷ and R⁸ each independently is:    -   hydrogen;    -   alkyl;    -   cycloalkyl;    -   cycloalkylalkyl;    -   haloalkyl;    -   haloalkoxy;    -   hydroxyalky;    -   alkoxyalkyl;    -   alkylsulfonyl;    -   alkylsulfonylalkyl;    -   aminocarbonyloxyalkyl;    -   hydroxycarbonylalkyl;    -   hydroxyalkyloxycarbonylalkyl;    -   aryl;    -   aralkyl;    -   arylsulfonyl;    -   heteroaryl;    -   heteroarylalkyl;    -   heteroarylsulfonyl;    -   heterocyclyl; or    -   heterocyclylalkyl.

In certain embodiments of formula X, D is absent

In certain embodiments of formula X, R¹ is ethyl, isopropyl, iodo,ethynyl or cyclopropyl.

In certain embodiments of formula X, X is —O— or —CH₂—.

In certain embodiments of formula X, R¹¹ is iodo, alkoxy, alkylsulfonylor —C≡C—R^(a).

In certain embodiments of formula X, R⁷ and R⁸ are hydrogen.

In certain embodiments of formula X, the compounds may be of formula XI:

wherein:R¹ is:

-   -   ethyl;    -   isopropyl;    -   iodo;    -   ethynyl; or    -   cyclopropyl;        R¹¹ is:    -   iodo;    -   alkoxy;    -   alkylsulfonyl; or    -   —C≡C—R^(a);        R^(g) is hydrogen or alkyl; and        R⁷ and R⁸ are as defined herein.

In certain embodiments of formula XI, R¹ is isopropyl.

In certain embodiments of formula XI, R¹¹ is iodo or —C≡C—R^(a).

In certain embodiments of formula XI, R⁷ and R⁸ are hydrogen.

In certain embodiments of formula X, the compounds may be of formulaXII:

wherein R⁷, R⁸ and R¹¹ are as defined herein.

Where any of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R^(a),R^(b), R^(c), R^(d), R^(e)R^(f) or R^(g) is alkyl or contains an alkylmoiety, such alkyl is preferably lower alkyl, i.e. C₁-C₆alkyl, and morepreferably C₁-C₄alkyl.

The invention also provides methods for treating a disease mediated by aP2X₃ receptor antagonist, a P2X_(2/3) receptor antagonist, or both, themethod comprising administering to a subject in need thereof aneffective amount of a compound of any of formulas (I) through (VIII).The disease may be genitorurinary disease or urinary tract disease. Inother instances the disease may be a disease is associated with pain.The urinary tract disease may be: reduced bladder capacity; frequenctmicturition; urge incontinence; stress incontinence; bladderhyperreactivity; benign prostatic hypertrophy; prostatitis; detrusorhyperreflexia; urinary frequency; nocturia; urinary urgency; overactivebladder; pelvic hypersensitivity; urethritis; prostatitits; pelvic painsyndrome; prostatodynia; cystitis; or idiophatic bladderhypersensitivity. The disease associated with pain may be: inflammatorypain; surgical pain; visceral pain; dental pain; premenstrual pain;central pain; pain due to burns; migraine or cluster headaches; nerveinjury; neuritis; neuralgias; poisoning; ischemic injury; interstitialcystitis; cancer pain; viral, parasitic or bacterial infection;post-traumatic injury; or pain associated with irritable bowel syndrome.The disease may be a respiratory disorder, such as chronic obstructivepulmonary disorder (COPD), asthma, or bronchospasm, or agastrointestinal (GI) disorder such as Irritable Bowel Syndrome (IBS),Inflammatory Bowel Disease (IBD), biliary colic and other biliarydisorders, renal colic, diarrhea-dominant IBS, pain associated with GIdistension.

Representative compounds in accordance with the methods of the inventionare shown in Table 1. TABLE 1 # Structure Name (Autonom ™) MP/M + H 1

5-(5-Ethynyl-2-isopropyl-4- methoxy-phenoxy)- pyrimidine-2,4-diamine170.0-173.6° C. 2

5-(2-Isopropyl-4-methoxy-5- phenylethynyl-phenoxy)-pyrimidine-2,4-diamine 195.1-196.2° C. 3

5-(2-Isopropyl-4-methoxy-5- prop-1-ynyl-phenoxy)- pyrimidine-2,4-diamine218.0-218.9° C. 4

5-(5-Ethynyl-4-fluoro-2- isopropyl-phenoxy)- pyrimidine-2,4-diamine 2875

5-[2-Isopropyl-4-methoxy-5- (3-methoxy-prop-1-ynyl)-phenoxy]-pyrimidine-2,4- diamine 174-175° C. 6

5-(2-Isopropyl-4-methoxy-5- pyridin-2-ylethynyl-phenoxy)-pyrimidine-2,4-diamine 222-223° C. 7

5-(2-Isopropyl-4-methoxy-5- pyridin-3-ylethynyl-phenoxy)-pyrimidine-2,4-diamine 210-211° C. 8

4-[5-(2,4-Diamino-pyrimidin- 5-yloxy)-4-isopropyl-2-methoxy-phenyl]-but-3-yn-1-ol 187-189° C. 9

5-[5-(2,4-Diamino-pyrimidin- 5-yloxy)-4-isopropyl-2-methoxy-phenyl]-pent-4- ynenitrile 190-191° C. 10

5-(2-Isopropyl-4-methoxy-5- pent-1-ynyl-phenoxy)- pyrimidine-2,4-diamine182-183° C. 11

5-(2-Isopropyl-4-methoxy-5- pyridin-4-ylethynyl-phenoxy)-pyrimidine-2,4-diamine 227.8-228.3° C. 12

5-(2-Isopropyl-4-methoxy-5- thiophen-3-ylethynyl-phenoxy)-pyrimidine-2,4- diamine 206.1-206.5° C. 13

5-[2-Isopropyl-4-methoxy-5- (3-methyl-3H-imidazol-4-ylethynyl)-phenoxy]- pyrimidine-2,4-diamine 204.1-205.1° C. 14

5-[5-(2,4-Diamino-pyrimidin- 5-yloxy)-4-isopropyl-2-methoxy-phenyl]-pent-4-yn-1- ol 169-170° C. 15

5-(4-Fluoro-2-isopropyl-5- prop-1-ynyl-phenoxy)- pyrimidine-2,4-diamine301 16

5-[2-Isopropyl-4-metboxy-5- (3-methylamino-prop-1-ynyl)-phenoxy]-pyrimidine-2,4- diamine 143-145° C. 17

3-[5-(2,4-Diamino-pyrimidin- 5-yloxy)-4-isopropyl-2-methoxy-pbenyl]-prop-2-yn-1-ol 227-229° C. 18

5-(2-Isopropyl-4-methoxy-5- trimethylsilanylethynyl-phenoxy)-pyrimidine-2,4- diamine 202.1-203.3° C. 19

5-(5-Cyclopropylethynyl-2- isopropyl-4-methoxy- phenoxy)-pyrimidine-2,4-diamine 225.5-226.8° C. 20

4-(2,4-Diamino-pyrimidin-5- yloxy)-2-ethynyl-5-isopropyl- phenol230.1-234.4° C. 21

5-(5-Ethynyl-2-isopropyl- phenoxy)-pyrimidine-2,4- diamine 150-151° C.22

5-[5-Ethynyl-4-(3-fluoro- benzyloxy)-2-isopropyl-phenoxy]-pyrimidine-2,4- diamine 161.0-163.0° C. 23

5-(5-Ethynyl-2-isopropyl-4- methoxy-benzyl)-pyrimidine- 2,4-diamine170.1-171.4° C. 24

5-(2-Ethyl-5-ethynyl-4- methoxy-phenoxy)- pyrimidine-2,4-diamine 285 25

5-(2,5-Diethynyl-4-methoxy- phenoxy)-pyrimidine-2,4- diamine 281 26

5-(2,5-Diethynyl-phenoxy)- pyrimidine-2,4-diamine 251 27

5-(5-Ethynyl-2-iodo-phenoxy)- pyrimidine-2,4-diamine 353 28

5-(2-Ethynyl-5-iodo-4- methoxy-phenoxy)- pyrimidine-2,4-diamine 383 29

5-(5-Iodo-2-isopropyl-3- methoxy-phenoxy)- pyrimidine-2,4-diamine 401 30

2-[4-(2,4-Diamino-pyrimidin- 5-yloxy)-2-ethynyl-5-isopropyl-phenoxy]-ethanol 189.3-191.7° C. 31

5-(5-Ethynyl-2-isopropyl-3- methoxy-phenoxy)- pyrimidine-2,4-diamine 29932

2-[4-Amino-5-(5-ethynyl-2- isopropyl-4-methoxy- phenoxy)-pyrimidin-2-ylamino]-ethanol 343 33

5-(5-Ethynyl-2-isopropyl-4- methoxy-phenoxy)-N*2*-(2-piperidin-1-yl-ethyl)-pyrimidine-2,4-diamine 410 33

N*2*-(2-Dimethylamino- ethyl)-5-(5-ethynyl-2- isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4- diamine 370 34

2-[4-Amino-5-(5-ethynyl-2- isopropyl-4-methoxy- phenoxy)-pyrimidin-2-ylamino]-propan-1-ol 357 35

5-(5-Ethynyl-2-isopropyl-4- methoxy-phenoxy)-N*2*-(2-morpholin-4-yl-ethyl)- pyrimidine-2,4-diamine 412 36

1-[4-Amino-5-(5-ethynyl-2- isopropyl-4-methoxy- phenoxy)-pyrimidin-2-ylamino]-propan-2-ol 357 37

5-(5-Ethynyl-2-isopropyl-4- methoxy-phenoxy)-N*2*-(1-methanesulfonyl-piperidin-4- yl)-pyrimidine-2,4-diamine 460 38

5-(5-Ethynyl-2-isopropyl-4- methoxy-phenoxy)-N*2*-(tetrahydro-pyran-4-yl)- pyrimidine-2,4-diamine 383 39

2-[4-Amino-5-(5-ethynyl-2- isopropyl-4-methoxy- phenoxy)-pyrimidin-2-ylamino]propane-1,3-diol 373 40

5-(4-Chloro-5-ethynyl-2- isopropyl-phenoxy)- pyrimidine-2,4-diamine 30341

3-[4-Amino-5-(5-ethynyl-2- isopropyl-4-methoxy- phenoxy)-pyrimidin-2-ylamino]-propan-1-ol 357Synthesis

Compounds of the present invention can be made by a variety of methodsdepicted in the illustrative synthetic reaction schemes shown anddescribed below.

The starting materials and reagents used in preparing these compoundsgenerally are either available from commercial suppliers, such asAldrich Chemical Co., or are prepared by methods known to those skilledin the art following procedures set forth in references such as Fieserand Fieser's Reagents for Organic Synthesis; Wiley & Sons: New York,1991, Volumes 1-15; Rodd's Chemistry of Carbon Compounds, ElsevierScience Publishers, 1989, Volumes 1-5 and Supplementals; and OrganicReactions, Wiley & Sons: New York, 1991, Volumes 1-40. The followingsynthetic reaction schemes are merely illustrative of some methods bywhich the compounds of the present invention can be synthesized, andvarious modifications to these synthetic reaction schemes can be madeand will be suggested to one skilled in the art having referred to thedisclosure contained in this application.

The starting materials and the intermediates of the synthetic reactionschemes can be isolated and purified if desired using conventionaltechniques, including but not limited to, filtration, distillation,crystallization, chromatography, and the like. Such materials can becharacterized using conventional means, including physical constants andspectral data.

Unless specified to the contrary, the reactions described hereinpreferably are conducted under an inert atmosphere at atmosphericpressure at a reaction temperature range of from about −78° C. to about150° C., more preferably from about 0° C. to about 125° C., and mostpreferably and conveniently at about room (or ambient) temperature,e.g., about 20° C.

Scheme A below illustrates one synthetic procedure usable to preparespecific compounds of formula (I) wherein L is a leaving group and R¹,R², R³ and R⁴ are as defined herein.

In step 1 of Scheme A, phenol a undergoes an O-alkylation by reactionwith an acetonitrile reagent to form cyano ether compound b. Compound bis then treated with Bredrick's reagent(t-butoxybis(dimethylamino)methane) in step 2 to form bisdimethylaminocompound c. In step 3 compound c is reacted with aniline to afford theaniline compound d. Compound d then undergoes reaction with guanidine instep 4 to provide phenoxy diamino pyrimidine e. Compound e, in step 5,is subject to iodination to yield iodophenoxy diamino pyrimidine f. Instep 6 compound f is treated with acetylene compound g to affordcompound h which is a compound of formula I in accordance with theinvention. Where R⁴ is H in compound h a suitable protecting group suchas trimethylsilyl may be included on acetylene compound g, which thenmay be subsequently removed. Alkylation or acylation of the amino groupsof compound h to provide desired R⁷ and R⁸ groups. In certainembodiments guanidine hydrochloride may be used in step 3 together withaniline to form phenoxy diamino pyrimidine e directly, without the needfor step 4. In certain embodiments compounds c and/or d need not beisolated as the reaction steps may be carried through in a singlereaction vessel.

Scheme B below illustrates another synthetic procedure usable to preparespecific compounds of formula (I) wherein R¹, R², R³, R⁴, R⁷ and R⁸ areas defined herein.

In Step 1 of Scheme B, benzaldehyde i is alkylated with the Grignardreagent derived from 4-chloro-5-iodo-2-methylsulfanyl-pyrimidine j orlike iodopyrimidine to provide an alpha-hydroxy benzyl pyrimidine k. Theiodopyrimidine used in this step may be prepared according to theprocedure described by T. Sakamoto, et al., Chem. Pharm. Bull., 34 1986,p. 2719. Numerous substituted benzaldehydes a are commercially availableor are readily prepared by techniques well known to those skilled in theart. In many instances, a “masked aldehyde”, such as an imine oroxazoline, may be used to allow introduction of desired functionalitiesto benzaldehyde i, after which the masked aldehyde is deprotected toprovide the free aldehyde group.

In step 2, alpha-hydroxy benzyl pyrimidine k is oxidized to provideketone compound l. In step 3, a first amination by reaction of amine mwith ketone compound l yields aminopyrimidine phenone compound n. Instep 4 the carbonyl group of compound n is reduced to a methylene groupto provide benzyl aminopyridine compound o. In step 5, an oxidation ofthe methylsulfanyl group of benzyl aminopyrimidine o is carried out toafford amino methanesulfonyl benzylpyrimidine p. A second aminationoccurs in step 6 in which amino methanesulfonyl benzylpyrimidine p istreated with amine q to displace the methanesulfonyl group and providediamino benzylpyrimidine r. The diamino benzylpyrimidine r is thensubject to iodination in step 7 followed y acetylation in step 8 byreaction with acetylene g, to afford diaminopyrimidine t, which is acompound of formula I in accordance with the invention.

Numerous variations on the above procedure are possible and will suggestthemselves to those skilled in the art upon review of this disclosure.Specific details for producing compounds of the invention are describedin the Examples section below.

Utility

The compounds of the invention are usable for the treatment of a widerange of genitorurinary diseases, conditions and disorders, includingurinary tract disease states associated with bladder outlet obstructionand urinary incontinence conditions such as reduced bladder capacity,frequency of micturition, urge incontinence, stress incontinence,bladder hyperreactivity, benign prostatic hypertrophy (BPH),prostatitis, detrusor hyperreflexia, urinary frequency, nocturia,urinary urgency, overactive bladder, pelvic hypersensitivity,urethritis, prostatitits, pelvic pain syndrome, prostatodynia, cystitis,and idiophatic bladder hypersensitivity, and other symptoms related tooveractive bladder.

The compounds of the invention are expected to find utility asanalgesics in the treatment of diseases and conditions associated withpain from a wide variety of causes, including, but not limited to,inflammatory pain, surgical pain, visceral pain, dental pain,premenstrual pain, central pain, pain due to burns, migraine or clusterheadaches, nerve injury, neuritis, neuralgias, poisoning, ischemicinjury, interstitial cystitis, cancer pain, viral, parasitic orbacterial infection, post-traumatic injuries (including fractures andsports injuries), and pain associated with functional bowel disorderssuch as irritable bowel syndrome.

Further, compounds of the invention are useful for treating respiratorydisorders, including chronic obstructive pulmonary disorder (COPD),asthma, bronchospasm, and the like.

Additionally, compounds of the invention are useful for treatinggastrointestinal disorders, including Irritable Bowel Syndrome (IBS),Inflammatory Bowel Disease (IBD), biliary colic and other biliarydisorders, renal colic, diarrhea-dominant IBS, pain associated with GIdistension, and the like.

Administration and Pharmaceutical Composition

The invention includes pharmaceutical compositions comprising at leastone compound of the present invention, or an individual isomer, racemicor non-racemic mixture of isomers or a pharmaceutically acceptable saltor solvate thereof, together with at least one pharmaceuticallyacceptable carrier, and optionally other therapeutic and/or prophylacticingredients.

In general, the compounds of the invention will be administered in atherapeutically effective amount by any of the accepted modes ofadministration for agents that serve similar utilities. Suitable dosageranges are typically 1-500 mg daily, preferably 1-100 mg daily, and mostpreferably 1-30 mg daily, depending upon numerous factors such as theseverity of the disease to be treated, the age and relative health ofthe subject, the potency of the compound used, the route and form ofadministration, the indication towards which the administration isdirected, and the preferences and experience of the medical practitionerinvolved. One of ordinary skill in the art of treating such diseaseswill be able, without undue experimentation and in reliance uponpersonal knowledge and the disclosure of this application, to ascertaina therapeutically effective amount of the compounds of the presentinvention for a given disease.

Compounds of the invention may be administered as pharmaceuticalformulations including those suitable for oral (including buccal andsub-lingual), rectal, nasal, topical, pulmonary, vaginal, or parenteral(including intramuscular, intraarterial, intrathecal, subcutaneous andintravenous) administration or in a form suitable for administration byinhalation or insufflation. The preferred manner of administration isgenerally oral using a convenient daily dosage regimen which can beadjusted according to the degree of affliction.

A compound or compounds of the invention, together with one or moreconventional adjuvants, carriers, or diluents, may be placed into theform of pharmaceutical compositions and unit dosages. The pharmaceuticalcompositions and unit dosage forms may be comprised of conventionalingredients in conventional proportions, with or without additionalactive compounds or principles, and the unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed. The pharmaceuticalcompositions may be employed as solids, such as tablets or filledcapsules, semisolids, powders, sustained release formulations, orliquids such as solutions, suspensions, emulsions, elixirs, or filledcapsules for oral use; or in the form of suppositories for rectal orvaginal administration; or in the form of sterile injectable solutionsfor parenteral use. Formulations containing about one (1) milligram ofactive ingredient or, more broadly, about 0.01 to about one hundred(100) milligrams, per tablet, are accordingly suitable representativeunit dosage forms.

The compounds of the invention may be formulated in a wide variety oforal administration dosage forms. The pharmaceutical compositions anddosage forms may comprise a compound or compounds of the presentinvention or pharmaceutically acceptable salts thereof as the activecomponent. The pharmaceutically acceptable carriers may be either solidor liquid. Solid form preparations include powders, tablets, pills,capsules, cachets, suppositories, and dispersible granules. A solidcarrier may be one or more substances which may also act as diluents,flavouring agents, solubilizers, lubricants, suspending agents, binders,preservatives, tablet disintegrating agents, or an encapsulatingmaterial. In powders, the carrier generally is a finely divided solidwhich is a mixture with the finely divided active component. In tablets,the active component generally is mixed with the carrier having thenecessary binding capacity in suitable proportions and compacted in theshape and size desired. The powders and tablets preferably contain fromabout one (1) to about seventy (70) percent of the active compound.Suitable carriers include but are not limited to magnesium carbonate,magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch,gelatine, tragacanth, methylcellulose, sodium carboxymethylcellulose, alow melting wax, cocoa butter, and the like. The term “preparation” isintended to include the formulation of the active compound withencapsulating material as carrier, providing a capsule in which theactive component, with or without carriers, is surrounded by a carrier,which is in association with it. Similarly, cachets and lozenges areincluded. Tablets, powders, capsules, pills, cachets, and lozenges maybe as solid forms suitable for oral administration.

Other forms suitable for oral administration include liquid formpreparations including emulsions, syrups, elixirs, aqueous solutions,aqueous suspensions, or solid form preparations which are intended to beconverted shortly before use to liquid form preparations. Emulsions maybe prepared in solutions, for example, in aqueous propylene glycolsolutions or may contain emulsifying agents, for example, such aslecithin, sorbitan monooleate, or acacia. Aqueous solutions can beprepared by dissolving the active component in water and adding suitablecolorants, flavors, stabilizers, and thickening agents. Aqueoussuspensions can be prepared by dispersing the finely divided activecomponent in water with viscous material, such as natural or syntheticgums, resins, methylcellulose, sodium carboxymethylcellulose, and otherwell known suspending agents. Solid form preparations include solutions,suspensions, and emulsions, and may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

The compounds of the invention may be formulated for parenteraladministration (e.g., by injection, for example bolus injection orcontinuous infusion) and may be presented in unit dose form in ampoules,pre-filled syringes, small volume infusion or in multi-dose containerswith an added preservative. The compositions may take such forms assuspensions, solutions, or emulsions in oily or aqueous vehicles, forexample solutions in aqueous polyethylene glycol. Examples of oily ornonaqueous carriers, diluents, solvents or vehicles include propyleneglycol, polyethylene glycol, vegetable oils (e.g., olive oil), andinjectable organic esters (e.g., ethyl oleate), and may containformulatory agents such as preserving, wetting, emulsifying orsuspending, stabilizing and/or dispersing agents. Alternatively, theactive ingredient may be in powder form, obtained by aseptic isolationof sterile solid or by lyophilization from solution for constitutionbefore use with a suitable vehicle, e.g., sterile, pyrogen-free water.

The compounds of the invention may be formulated for topicaladministration to the epidermis as ointments, creams or lotions, or as atransdermal patch. Ointments and creams may, for example, be formulatedwith an aqueous or oily base with the addition of suitable thickeningand/or gelling agents. Lotions may be formulated with an aqueous or oilybase and will in general also containing one or more emulsifying agents,stabilizing agents, dispersing agents, suspending agents, thickeningagents, or coloring agents. Formulations suitable for topicaladministration in the mouth include lozenges comprising active agents ina flavored base, usually sucrose and acacia or tragacanth; pastillescomprising the active ingredient in an inert base such as gelatine andglycerine or sucrose and acacia; and mouthwashes comprising the activeingredient in a suitable liquid carrier.

The compounds of the invention may be formulated for administration assuppositories. A low melting wax, such as a mixture of fatty acidglycerides or cocoa butter is first melted and the active component isdispersed homogeneously, for example, by stirring. The moltenhomogeneous mixture is then poured into convenient sized molds, allowedto cool, and to solidify.

The compounds of the invention may be formulated for vaginaladministration. Pessaries, tampons, creams, gels, pastes, foams orsprays containing in addition to the active ingredient such carriers asare known in the art to be appropriate.

The subject compounds may be formulated for nasal administration. Thesolutions or suspensions are applied directly to the nasal cavity byconventional means, for example, with a dropper, pipette or spray. Theformulations may be provided in a single or multidose form. In thelatter case of a dropper or pipette, this may be achieved by the patientadministering an appropriate, predetermined volume of the solution orsuspension. In the case of a spray, this may be achieved for example bymeans of a metering atomizing spray pump.

The compounds of the invention may be formulated for aerosoladministration, particularly to the respiratory tract and includingintranasal administration. The compound will generally have a smallparticle size for example of the order of five (5) microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization. The active ingredient is provided in a pressurizedpack with a suitable propellant such as a chlorofluorocarbon (CFC), forexample, dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane, or carbon dioxide or other suitable gas. Theaerosol may conveniently also contain a surfactant such as lecithin. Thedose of drug may be controlled by a metered valve. Alternatively theactive ingredients may be provided in a form of a dry powder, forexample a powder mix of the compound in a suitable powder base such aslactose, starch, starch derivatives such as hydroxypropylmethylcellulose and polyvinylpyrrolidine (PVP). The powder carrier will form agel in the nasal cavity. The powder composition may be presented in unitdose form for example in capsules or cartridges of e.g., gelatine orblister packs from which the powder may be administered by means of aninhaler.

When desired, formulations can be prepared with enteric coatings adaptedfor sustained or controlled release administration of the activeingredient. For example, the compounds of the present invention can beformulated in transdermal or subcutaneous drug delivery devices. Thesedelivery systems are advantageous when sustained release of the compoundis necessary and when patient compliance with a treatment regimen iscrucial. Compounds in transdermal delivery systems are frequentlyattached to an skin-adhesive solid support. The compound of interest canalso be combined with a penetration enhancer, e.g., Azone(1-dodecylazacycloheptan-2-one). Sustained release delivery systems areinserted subcutaneously into the subdermal layer by surgery orinjection. The subdermal implants encapsulate the compound in a lipidsoluble membrane, e.g., silicone rubber, or a biodegradable polymer,e.g., polylactic acid.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

Other suitable pharmaceutical carriers and their formulations aredescribed in Remington: The Science and Practice of Pharmacy 1995,edited by E. W. Martin, Mack Publishing Company, 19th edition, Easton,Pa. Representative pharmaceutical formulations containing a compound ofthe present invention are described below.

EXAMPLES

The following preparations and examples are given to enable thoseskilled in the art to more clearly understand and to practice thepresent invention. They should not be considered as limiting the scopeof the invention, but merely as being illustrative and representativethereof.

Unless otherwise stated, all temperatures including melting points(i.e., MP) are in degrees celcius (° C.). It should be appreciated thatthe reaction which produces the indicated and/or the desired product maynot necessarily result directly from the combination of two reagentswhich were initially added, i.e., there may be one or more intermediateswhich are produced in the mixture which ultimately leads to theformation of the indicated and/or the desired product. The followingabbreviations may be used in the Examples.

Abbreviations

DCM dichloromethane/methylene chloride

DMF N,N-dimethylformamide

DMAP 4-dimethylaminopyridine

EtOAc ethyl acetate

EtOH ethanol

gc gas chromatography

HMPA hexamethylphosphoramide

hplc high performance liquid chromatography

mCPBA m-chloroperbenzoic acid

MeCN acetonitrile

NMP N-methylpyrrolidinone

TEA triethylamine

THF tetrahydrofuran

LDA lithium diisopropylamine

TLC thin layer chromatography

Example 15-(5-Ethynyl-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine

The synthetic procedure used in this Example is outlined in Scheme C.

Step 1 2-Isopropyl-4-methoxy-phenol

To a cooled solution of 1-(2-Hydroxy-5-methoxy-phenyl)-ethanone (10.0 g)in 80 mL of THF was gradually added 46.4 g of 3M solution of MeMgCl inTHF at a rate such that the reaction mixture temperature did not exceed25 degrees C. Following addition of the MeMgCl solution, the reactionmixture was stirred at ambient temperature for 18 hours. To the stirredsolution was then added 10% palladium on carbon (1.02 g, 50% water wet)suspended in 4 mL of THF. The reaction mixture was placed under ahydrogen atmosphere at 5 psig and cooling was applied to maintain atemperature of approximately 25° C. To the cooled mixture was graduallyadded concentrated HCl (20 mL) while maintaining the reactiontemperature at 25° C. The resultant mixture was stirred at ambienttemperature for 18 hours, then treated with 45 mL water and filteredthrough a bed of Celite to remove suspended catalyst. The filter cakewas rinsed with EtOAc and the combined filtrate was separated. Theorganic phase was washed with water, then concentrated under reducedpressure to give 10.4 g of 2-isopropyl-4-methoxy-phenol, MS (M+H)=167.This product was dissolved in 2-butanone (20.4 g) and the crude solutionwas employed directly in the next step.

Step 2 (2-Isopropyl-4-methoxy-phenoxy)-acetonitrile

A stirred slurry of toluene-4-sulfonic acid cyanomethyl ester (13.0 g),potassium carbonate (13.0 g) and 2-isopropyl-4-methoxyphenol (9.57 g) in85 mL of 2-butanone was heated to 55-60 degrees C. for 4 days, thenheated to relux for 18 hours. The resultant slurry was cooled andfiltered to remove solids. The filtrate was concentrated under reducedpressure and the residue was redissolved in toluene. The toluenesolution was extracted with 1N KOH, and the organic phase wasconcentrated under reduced pressure to give 20.6 g of a 1:1 (by weight)solution of (2-Isopropyl-4-methoxy-phenoxy)-acetonitrile in toluene,which was used directly in the next step. A anliquot (0.967 g) of thissolution was concentrated to dryness to give 0.509 g of crude(2-Isopropyl-4-methoxy-phenoxy)-acetonitrile, MS (M+H)=206.

Step 3 5-(2-Isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine

A 1:1 (by weight) solution of toluene and(2-Isopropyl-4-methoxy-phenoxy)-acetonitrile (10.6 g of the nitrilecompound) was concentrated under reduced pressure and the residue wastreated with 10.8 g of tert-butoxybis(dimethylamino)methane (Bredrick'sReagent). The resulting mixture was dissolved in 22 mL of DMF and thesolution was heated to 110 degrees C. for 2 hours. The DMF solution wascooled and transferred onto 14.7 g of aniline hydrochloride. Theresulting mixture was heated to 120 degrees C. for 22 hours, thencooled, diluted with 25 mL toluene, then with 70 mL of water. Theorganic layer was separated, washed with water, and concentrated underreduced pressure. The residue was transferred into 25 mL DMF, and theDMF solution was transferred onto 6.01 g of guanidine carbonate. Theresulting mixture was heated to 120 degrees C. for 3 days, then cooled,diluted with 10 mL of EtOAc, then reheated to 60 degrees C. Water (75.1m L) was added and the resultant mixture was allowed to cool to ambienttemperature. The precipitated solid was collected by filtration, rinsedwith isopropanol and dried under vacuum at 50 degrees to give 9.62 g of5-(2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine, m.p. 170-171degrees C., MS (M+H)=275.

Step 4 5-(5-Iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine

To a solution of5-(2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (6.50 g) in mLglacial Acetic acid was added a solution of 9.205 g ICl (iodinemonochloride) in 8 mL of acetic acid, with addition carried out at arate such that the temperature of the resulting mixture did not exceed24 degrees C. Water (11.0 mL) was added and the resultant mixture wasstirred at 25 degrees C. for 42 hours. Excess ICl was decomposed by theaddition of aqueous solution of sodium bisulfite (3.5 mL) at a rate suchthat the temperature of the reaction mixture did not exceed 20 degreesC. Water (40 mL) was added, and the precipitate was collected byfiltration and air-dried to give 8.86 g of crude5-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine. Asuspension of the crude product in 90 mL water was made basic byaddition of 50% NaOH, and the resulting solution was extracted into warmEtOAc. The combined organic layers were filtered and EtOAc was replacedby isopropanol via distillation. To the hot isopropanol solution wasadded 3.4 mL of 6N HCl and the resultant mixture was cooled slowly to 15degrees C. Crystals of the resulting HCl salt were isolated byfiltration, rinsed with isopropanol, and dried under vacuum at 70degrees C. to give 6.08 g (58.8%) of5-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diaminehydrochloride salt, m.p.=262.0-263.0° C., MS (M+H)=401.

Step 55-(2-Isopropyl-4-methoxy-5-trimethylsilanylethynyl-phenoxy)-pyrimidine-2,4-diamine

5-(5-Iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (2.0 g,5 mmol), bis(triphenylphosphine)-Palladium dichloride (700 mg, 1 mmol)and CuI (100 mg, 0.5 mmol) were added to 14 mL dry THF under nitrogen.Trimethylsilyl acetylene (1.4 mL, 10 mmol) was added, followed by 7 mLdiisopropylethylamine. The reaction mixture was stirred at 50° C. undernitrogen for 17 hours, then was allowed to cool for two hours withstirring. The reaction mixture was poured into 15% aqueous NHCl andextracted into EtOAc. The combined organic layers were washed withbrine, dried over MgSO₄, filtered and concentrated under reducedpressure. The residue was chromatographed on 150 g of flash silica(2%-4% MeOH/CH₂Cl₂) to give 1.70 g of5-(2-Isopropyl-4-methoxy-5-trimethylsilanylethynyl-phenoxy)-pyrimidine-2,4-diamine,MS (M+H)=371.

Step 65-(5-Ethynyl-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine

5-(2-Isopropyl-4-methoxy-5-trimethylsilanylethynyl-phenoxy)-pyrimidine-2,4-diamine(0.75 g, 2 mmol) and Cesium Fluoride (0.46 g, 3 mmol) were added to 10mL of dry THF under nitrogen, and the reaction mixture was stirred for 6hours at room temperature. The reaction mixture was poured into waterand extracted with EtOAc. The combined organic layers were washed withbrine, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was chromatographed on 50 g of flash silica (3%-6%MeOH/CH₂Cl₂) to give 0.54 g of5-(5-ethynyl-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine, MS(M+H)=299.

Example 2 4-(2,4-Diamino-pyrimidin-5-yloxy)-2-ethynyl-5-isopropyl-phenol

5-(2-Isopropyl-4-methoxy-5-trimethylsilanylethynyl-phenoxy)-pyrimidine-2,4-diamine(0.65 g, 1.75 mmol) was added to 40 mL methylene chloride at ice bathtemperature and under nitrogen. Boron tribromide (7 mL) was added andthe reaction mixture was stirred at ice bath temperature for 1.5 hours,and then for 20 hours at room temperature. The reaction mixture wasadded to saturated aqueous NaHCO₃, and the resulting mixture wasextracted with chloroform. The combined organic layers were washed withbrine, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was chromatographed on 50 g of flash silica (2%-6%MeOH/CH₂Cl₂) to give 103 mg of4-(2,4-diamino-pyrimidin-5-yloxy)-2-ethynyl-5-isopropyl-phenol, MS(M+H)=285.

Example 35-(2-Isopropyl-4-methoxy-5-prop-1-ynyl-phenoxy)-pyrimidine-2,4-diamine

5-(5-Iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (1.0 g,2.5 mmol), bis(triphenylphosphine)palladium dichloride (290 mg, 0.25mmol), 1-(trimethylsilyl)-1-propyne (0.44 mL, 3 mmol) and tetrabutylammonium fluoride (3 mL, 3 mmol) were added to 20 mL dry THF undernitrogen. The reaction mixture was stirred under nitrogen at 50° C. for22 hours, then 150 mg of bis(triphenylphosphine)-Palladium dichloride,0.22 mL of 1-(trimethylsilyl)-1-propyne and 1.5 mL tetrabutyl ammoniumfluoride, and 0.1 mL ethanol were added to the reaction mixture. Thereaction mixture was stirred under nitrogen for 18 hours at 50° C. Thereaction mixture was cooled and poured into saturated aqueous NaHCO₄ andextracted into EtOAc. The combined organic layers were washed withbrine, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was chromatographed on 125 g of flash silica(2%-4% MeOH/CH₂Cl₂) to give 925 mg of5-(2-isopropyl-4-methoxy-5-prop-1-ynyl-phenoxy)-pyrimidine-2,4-diamine,MS (M+H)=313.

Example 45-(5-Cyclopropylethynyl-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine

5-(5-Iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (873 g,2 mmol), bis(triphenylphosphine)palladium dichloride (140 mg, 0.2 mmol),and CuI (19 mg, 0.1 mmol) were added to 15 mL of degasseddiisopropylamine under nitrogen in a screw cap flask.Ethynylcyclopropane (0.25 mL, 3 mmol) was added, and the flask wassealed and heated to 70° C. for 18 hours. The reaction mixture wascooled, poured into water, and extracted into dichloromethane. Thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered and concentrated under reduced pressure. The residue waschromatographed on 100 g of flash silica (2%-3% MeOH/CH₂Cl₂) to give 605mg of5-(5-cyclopropylethynyl-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine.MP 225.5-226.8° C.; MS (M+H)=339.

Similarly prepared using the appropriate substituted ethynes, were:

-   5-(2-Isopropyl-4-methoxy-5-phenylethynyl-phenoxy)-pyrimidine-2,4-diamine;    MP 195.1-196.2° C.;-   5-[2-Isopropyl-4-methoxy-5-(3-methoxy-prop-1-ynyl)-phenoxy]-pyrimidine-2,4-diamine;    MP 174-175° C.;-   5-(2-Isopropyl-4-methoxy-5-pyridin-2-ylethynyl-phenoxy)-pyrimidine-2,4-diamine;    MP 222-223° C.;-   5-(2-Isopropyl-4-methoxy-5-pyridin-3-ylethynyl-phenoxy)-pyrimidine-2,4-diamine;    210-211° C.;-   4-[5-(2,4-Diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-phenyl]-but-3-yn-1-ol;    MP 187-189° C.;-   5-[5-(2,4-Diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-phenyl]-pent-4-ynenitrile;    MP 190-191° C.;-   5-(2-Isopropyl-4-methoxy-5-pent-1-ynyl-phenoxy)-pyrimidine-2,4-diamine;    MP 182-183° C.;-   5-(2-Isopropyl-4-methoxy-5-pyridin-4-ylethynyl-phenoxy)-pyrimidine-2,4-diamine;    MP 227.8-228.3° C.;-   5-(2-Isopropyl-4-methoxy-5-thiophen-3-ylethynyl-phenoxy)-pyrimidine-2,4-diamine;    MP 206.1-206.5° C.;-   5-[2-Isopropyl-4-methoxy-5-(3-methyl-3H-imidazol-4-ylethynyl)-phenoxy]-pyrimidine-2,4-diamine;    MP 204.1-205.1° C.;-   5-[5-(2,4-Diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-phenyl]-pent-4-yn-1-ol;    MP 169-170° C.;-   5-[2-Isopropyl-4-methoxy-5-(3-methylamino-prop-1-ynyl)-phenoxy]-pyrimidine-2,4-diamine;    143-145° C.; and-   3-[5-(2,4-Diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-phenyl]-prop-2-yn-1-ol;    MP 227-229° C.

Example 55-(4-Fluoro-2-isopropyl-5-prop-1-ynyl-phenoxy)-pyrimidine-2,4-diamine

The synthetic procedure used in this Example is outlined in Scheme D.

Step 1 5-(4-Fluoro-5-iodo-2-isopropyl-phenoxy)-pyrimidine-2,4-diamine

5-(4-Fluoro-2-isopropyl-phenoxy)-pyrimidine-2,4-diamine (400 mg, 1.53mmol, prepared using the procedure of example 1) was dissolved in dryTHF at ice bath temperature, and trifluoromethylsulfonic acid (0.67 mL,7.63 mmol) was added. After stirring for 10 minutes, N-iodosuccinimide(378 g, 1.68 mmol) was added in portions. The ice bath was removed andthe reaction mixture was stirred for three hours. The reaction mixturewas then poured over ice and extracted with dichloromethane. Thecombined organic layers were washed with 10% aqueous sodium bisulfitesolution and water, dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue was chromatographed on silica (95%:5%:1%CH₂Cl₂:MeOH:NH₄OH) to give 338 mg of5-(4-fluoro-5-iodo-2-isopropyl-phenoxy)-pyrimidine -2,4-diamine, MS(M+H)=389.

Step 25-(4-Fluoro-2-isopropyl-5-prop-1-ynyl-phenoxy)-pyrimidine-2,4-diamine

Using the procedure of Example 3,5-(4-fluoro-5-iodo-2-isopropyl-phenoxy)-pyrimidine-2,4-diamine (MS(M+H)=301) was prepared from5-(4-fluoro-5-iodo-2-isopropyl-phenoxy)-pyrimidine -2,4-diamine

Similarly prepared from5-(4-fluoro-5-iodo-2-isopropyl-phenoxy)-pyrimidine -2,4-diamine usingthe procedure of step 8 of example 1 was5-(5-Ethynyl-4-fluoro-2-isopropyl-phenoxy)-pyrimidine -2,4-diamine, MS(M+H)=289.

Example 6 5-(2,5-Diethynyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine

The synthetic procedure used in this Example is outlined in Scheme E.

Step 1 2,5-Diiodo-4-methoxy-phenol

1,4-Diiodo-2,5-dimethoxy-benzene (3.65 g, 9.36 mmol) was added to 100 mLof dichloromethane and stirred under nitrogen at ice bath temperature.Boron tribromide (10.3 mL, 10.3 mmol) was added dropwise, and thereaction mixture was stirred at ice bath temperature for 20 hours. Thereaction was quenched by dropwise addition of methanol, and the reactionmixture was poured into water and extracted into dichloromethane. Thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered and concentrated under reduced pressure to give 2.86 g of2,5-Diiodo-4-methoxy-phenol, MS (M+H)=377.

Step 2 (2,5-Diiodo-4-methoxy-phenoxy)-acetonitrile

2,5-Diiodo-4-methoxy-phenol (2.8 g, 7.5 mmol) and potassium carbonate(2.1 g) were added to 30 mL of stirring acetone at room temperature andunder nitrogen. Bromoacetonitrile (0.575 mL, 8.25 mmol) was added, andthe reaction mixture was heated to 60° C. and stirred under nitrogen for8 hours, then stirred for 18 hours under nitrogen at room temperature.The reaction mixture concentrated under reduced pressure, and theresidue was poured into water and extracted into EtOAc. The combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was chromatographed on150 g of flash silica (5%-20% EtOAc/hexanes) to give 2.86 g of(2,5-Diiodo-4-methoxy-phenoxy)-acetonitrile, MS (M+H)=416.

Step 3 2-(2,5-Diiodo-4-methoxy-phenoxy)-but-2-enenitrile

(2,5-Diiodo-4-methoxy-phenoxy)-acetonitrile (2.8 g, 6.75 mmol) andtert-butoxybis(dimethylamino)methane (Bredrick's reagent, 7 mL, 33.7mmol) were combined and heated to 105° C. under nitrogen for 2 hours.The reaction mixture was cooled and concentrated under reduced pressureto yield 3.47 g of crude2-(2,5-diiodo-4-methoxy-phenoxy)-but-2-enenitrile, which was useddirectly in the following step.

Step 4 5-(2,5-Di iodo-4-methoxy-phenoxy)-pyrimidine-2,4-diamine

2-(2,5-Diiodo-4-methoxy-phenoxy)-but-2-enenitrile (3.47 g, 6.75 mmol)and aniline hydrochloride (3.5 g, 27 mmol) were dissolved in 27 mLethanol. The reaction mixture was heated to 85° C. and stirred undernitrogen for 18 hours. The reaction mixture was cooled and 25% NaOCH₃ inmethanol (7.3 mL) was added, followed by guanidine hydrochloride (3.2g), and ethanol (10 mL). The reaction mixture was heated to 100° C. for21 hours, then cooled and concentrated under reduced pressure. Theresidue was poured into water and extracted with dichloromethane. Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give 1.2 g of5-(2,5-Diiodo-4-methoxy-phenoxy)-pyrimidine-2,4-diamine, MS (M+H)=485.

Step 55-(4-Methoxy-2,5-bis-trimethylsilanylethynyl-phenoxy)-pyrimidine-2,4-diamine

5-(2,5-Diiodo-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (1.2 g, 2.5mmol), bis(triphenylphosphine)palladium dichloride (175 mg, 2.5 mmol),and CuI (25 mg, 0.125 mmol) were added to 7 mL dry THF.Trimethylsilylacetylene ((0.48 mL, 3.3 mmol), and diisopropylethylamine(3.5 mL) were added, and the reaction mixture was heated to 50° C. undernitrogen for 27 hours. The reaction mixture was cooled, poured into 15%aqueous NH₄Cl and extracted into EtOAc. The combined organic layers werewashed with brine, dried over MgSO₄, filtered and concentrated underreduced pressure to give crude5-(4-Methoxy-2,5-bis-trimethylsilanylethynyl-phenoxy)-pyrimidine-2,4-diamine together with monoacetylenes5-(2-iodo-4-methoxy-5-trimethylsilanylethynyl-phenoxy)-pyrimidine-2,4-diamineand5-(5-iodo-4-methoxy-2-trimethylsilanylethynyl-phenoxy)-pyrimidine-2,4-diamine.This residue was chromatographed on 125 g of flash silica (6:1:1CH₂Cl₂:MeOH:NH₄OH) to give 450 mg of5-(4-Methoxy-2,5-bis-trimethylsilanylethynyl-phenoxy)-pyrimidine-2,4-diamine,MS (M+H)=425.

Step 6 5-(2,5-Diethynyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine

5-(4-Methoxy-2,5-bis-trimethylsilanylethynyl-phenoxy)-pyrimidine-2,4-diamine(450 mg, 1.06 mmol) and potassium fluoride (246 mg, 4.2 mmol) were addedto 7 mL dry DMF under nitrogen. Two drops of 48% HBr were added, and thereaction mixture was stirred under nitrogen at room temperature for fourhours. The reaction mixture was poured into water and extracted withEtOAc. The combined organic layers were dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was recrystallized from10% MeOH in dichloromethane to give 228 g of5-(2,5-Diethynyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine,MP=163.2-164.1° C., MS (M+H)=281.

The fractions from step 5 containing monoacetylenes5-(2-iodo-4-methoxy-5-trimethylsilanylethynyl-phenoxy)-pyrimidine-2,4-diamineand5-(5-iodo-4-methoxy-2-trimethylsilanylethynyl-phenoxy)-pyrimidine-2,4-diaminewere deprotected in a similar manner to provide5-(5-Ethynyl-2-iodo-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (MS(M+H)=383) and5-(2-Ethynyl-5-iodo-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (MS(M+H)=383) respectively.

Example 7 5-(2,5-Diethynyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine and5-(5-Ethynyl-2-iodo-4-methoxy-phenoxy)-pyrimidine-2,4-diamine

The synthetic procedure used in this Example is outlined in Scheme F.

A suspension of 3-iodophenyl (11.0 g, 50 mmol) and silver acetate (10.02g, 60 mmol) in 400 mL dichloromethane was treated dropwise with asolution of iodine (12.7 g, 50 mmol in 250 mL dichloromethane). Theresulting mixture was stirred for 18 hours at room temperature, thenfiltered through a Celite pad. The filtrate was concentrated underreduced pressure and the residue was chromatographed on silica (30%dichloromethane in hexanes) to give 7.7 g of 2,5-diiodo-phenol, MS(M+H)=346.

Step 2 (2,5-Diiodo-phenoxy)-acetonitrile

A mixture of 2,5-diiodo-phenol (3.9 g, 11.28 mmol), bromoacetonitrile(2.03 g, 16.91 mmol) and potassium carbonate (3.11 g, 22.55 mmol) in 7mL acetonitrile was sealed in a stoppered flask and stirred at roomtemperature for 18 hours. The reaction mixture was poured into water andextracted with EtOAc. The combined organic layers were washed with waterand brine, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was chomatographed on silica gel (30%-70%CH₂Cl₂/hexanes) to give 2.78 g of (2,5-Diiodo-phenoxy)-acetonitrile.

Step 3 5-(2,5-Diiodo-4-methoxy-phenoxy)-pyrimidine-2,4-diamine

A mixture of (2,5-diiodo-phenoxy)-acetonitrile (1.15 g, 2.99 mmol) andtert-butoxybis(dimethylamino)methane (Bredrick's reagent, 2.08 g, 11.95mmol) was heated to 100° C. under nitrogen for 18 hours. The reactionmixture was cooled and concentrated under reduced pressure. To theresidue was added aniline hydrochloride (1.162 g, 8.97 mmol) and EtOH(20 mL). The resulting mixture was heated to reflux for 20 hours undernitrogen atmosphere. The reaction mixture was cooled to room temperatureand concentrated under reduced pressure. A mixture of guanidinehydrochloride (1.43 g, 14.95 mmol) and 25% NaOCH₃ in methanol (3.3 mL,14.95 mmol) in 7 mL ethanol was added to the residue, and the resultingmixture was heated to reflux under nitrogen for 18 hours. The reactionmixture was cooled, poured into water and extracted with EtOAc. Thecombined organic layers were washed with water and brine, dried overNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas chomatographed on silica gel (30% CH₂Cl₂ in hexanes with 0.1% NH₄OH)to give 0.64 g of5-(2,5-diiodo-4-methoxy-phenoxy)-pyrimidine-2,4-diamine, MP=136-138° C.MS (M+H)=455.

Step 45-(2,5-Bis-trimethylsilanylethynyl-phenoxy)-pyrimidine-2,4-diamine and5-(2-Iodo-5-trimethylsilanylethynyl-phenoxy)-pyrimidine-2,4-diamine

To a mixture of 5-(2,5-diiodo-4-methoxy-phenoxy)-pyrimidine-2,4-diamine(2.043 g, 4.5 mmol), bis(triphenylphosphine)palladium dichloride (0.316g, 0.45 mmol) and CuI (43 mg, 0.225 mmol) in 14 mL dry THF was addedtrimethylsilylacetylene (0.441 g, 4.5 mmol), followed bydiisopropylethylamine (7 mL). The reaction mixture was heated at 50° C.under nitrogen atmosphere for 20 hours. The reaction mixture was cooled,poured into saturated aqueous NH₄Cl and extracted with dichloromethane.The combined organic layers were washed with water and brine, dried overMgSO₄, filtered and concentrated under reduced pressure. The residue waschromatographed on silica (4% MeOH in CH₂Cl₂ with 0.1% NH₄OH) to give0.350 g of5-(2,5-Bis-trimethylsilanylethynyl-phenoxy)-pyrimidine-2,4-diamine as afirst fraction, and 0.41 g of5-(2-Iodo-5-trimethylsilanylethynyl-phenoxy)-pyrimidine-2,4-diamine as asecond fraction.

Step 5 5-(2,5-Diethynyl-phenoxy)-pyrimidine-2,4-diamine and5-(5-Ethynyl-2-iodo-phenoxy)-pyrimidine-2,4-diamine

A mixture of5-(2-Iodo-5-trimethylsilanylethynyl-phenoxy)-pyrimidine-2,4-diamine (0.4g, 2.36 mmol), potassium fluoride (41 mg, 7.07 mmol) and HBr (2 drops of48% aqueous solution) in DMF was stirred at room temperature for 30minutes. The reaction mixture was diluted with water and EtOAc andbasified with 1 mL NH₄OH. The organic layer was separated, washed withwater and brine, dried over MgSO₄, filtered and concentrated underreduced pressure. The residue was chromatographed on silica (4% MeOH inCH₂Cl₂ with 0.1% NH₄OH) to give 0.36 g of5-(5-Ethynyl-2-iodo-phenoxy)-pyrimidine-2,4-diamine, MP=156-159° C., MS(M+H)=352.

Similarly prepared from5-(2,5-Bis-trimethylsilanylethynyl-phenoxy)-pyrimidine -2,4-diamine was5-(2,5-Diethynyl-phenoxy)-pyrimidine-2,4-diamine, MP=125=129° C., MS(M+H)=251.

Example 85-(5-Iodo-2-isopropyl-3-methoxy-phenoxy)-pyrimidine-2,4-diamine

The synthetic procedure used in this Example is outlined in Scheme G.

Step 1 N-(3,5-Dimethoxy-phenyl)-2,2,2-trifluoro-acetamide

To 3,5-dimethoxyaniline (20 g, 131 mmol) dissolved in anhydroustetrahydrofuran (90 mL) was added 4-(dimethylamino)pyridine (1.6 g, 13.1mmol) and ethyl trifluoroacetate (47 mL, 392 mmol). After refluxing 48hours, the cooled reaction mixture was concentrated and partitionedbetween ethyl acetate (300 mL) and 2N hydrochloric acid (100 mL). Theethyl acetate layer was washed with water (100 mL), dried usinganhydrous sodium sulfate, and concentrated to yieldN-(3,5-Dimethoxy-phenyl)-2,2,2-trifluoro-acetamide (31.8 g, 98%) as paleyellow solid.

Step 2 N-(4-Acetyl-3,5-dimethoxy-phenyl)-2,2,2-trifluoro-acetamide

To a solution of N-(3,5-Dimethoxy-phenyl)-2,2,2-trifluoro-acetamide(31.8 g, 130 mmol) in anhydrous dichloroethane (450 mL), cooled in anice bath, was added a solution of tin (IV) chloride (29.9 mL, 260 mmoldissolved in 30 mL anhydrous dichloroethane) dropwise over 10 minutes.Acetyl chloride (9.1 mL, 130 mmol) was added slowly, maintaining thetemperature of the reaction below 5° C. After stirring 3 hours at roomtemperature, the reaction was cooled in an ice bath. Water (300 mL) wasadded, maintaining the temperature of the reaction below 25° C., and thereaction was stirred at room temperature for 18 hours. The reactionmixture was extracted with dichloromethane, and the organic layer wasseparated, washed with water, dried over sodium sulfate, filtered andevaporated under reduced pressure. The residue was purified by silicagel column chromatography eluting with 20% to 30% hexanes/ethyl acetateto yield N-(4-Acetyl-3,5-dimethoxy-phenyl)-2,2,2-trifluoro-acetamide(4.8 g, 13%) as a white solid.

Step 3 1-(4-Amino-2,6-dimethoxy-phenyl)-ethanone

To N-(4-Acetyl-3,5-dimethoxy-phenyl)-2,2,2-trifluoro-acetamide (4.3 g,14.8 mmol) dissolved in methanol (90 mL) was added anhydrous potassiumcarbonate (4.67 g, 33.8 mmol). After refluxing for 18 hours, thereaction mixture was cooled and concentrated under reduced pressure. Theconcentrate was extracted with ethyl acetate and the organic layer waswashed with brine, dried using anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to yield1-(4-Amino-2,6-dimethoxy-phenyl)-ethanone (2.5 g, 87%) as a pale yellowsolid.

Step 4 2-(4-Amino-2,6-dimethoxy-phenyl)-propan-2-ol

To a solution of methyl magnesium bromide (3M in ether, 16.8 mL, 50.5mmol) in anhydrous tetrahydrofuran (20 mL), cooled in an ice bath, wasadded 1-(4-amino-2,6-dimethoxy-phenyl)-ethanone (2.19 g, 11.2mmol-dissolved in 65 mL anhydrous tetrahydrofuran), maintaining thereaction temperature below 10° C. After stirring 4 hours at roomtemperature, 10% ammonium chloride (20 mL) was added, maintaining thetemperature of the reaction below 20° C. (with the use of an ice bath)during the addition. The mixture was diluted with water and extractedwith ethyl acetate. The ethyl acetate layer was washed with brine, driedusing anhydrous sodium sulfate, filtered and concentrated to yield2-(4-Amino-2,6-dimethoxy-phenyl)-propan-2-ol (2.23 g, 94%) as a paleyellow solid.

Step 5 4-Isopropenyl-3,5-dimethoxy-phenylamine

A solution of 2-(4-Amino-2,6-dimethoxy-phenyl)-propan-2-ol (2.2 g, 10.4mmol) in chloroform (100 mL) was refluxed overnight. The cooled reactionmixture was concentrated under reduced pressure to yield4-Isopropenyl-3,5-dimethoxy-phenylamine, which was used directly in thefollowing step.

Step 6 4-Isopropyl-3,5-dimethoxy-phenylamine

A solution of 4-Isopropenyl-3,5-dimethoxy-phenylamine (take directlyfrom step 5) in ethanol (200 mL) was hydrogenated overnight at roomtemperature and 1 psig of H₂ gas using 10% palladium on charcoalcatalyst (200 mg). The reaction was filtered through Celite and the padwas washed with additional ethanol. Concentration of the filtrate andpurification by silica gel column chromatography eluting with 70/30hexane/ethyl acetate yielded 4-Isopropyl-3,5-dimethoxy-phenylamine (1.4g, 69%) as a pale pink solid, MS (M+H)=196.

Step 7 5-Iodo-2-isopropyl-1,3-dimethoxy-benzene

To a suspension of 4-Isopropyl-3,5-dimethoxy-phenylamine (1.28 g, 6.56mmol) in 15% hydrochloric acid (20 mL) at 0° C. was added sodium nitrite(0.54 g, 7.87 mmol-dissolved in 4 mL water) dropwise. After stirring 20minutes, potassium iodide (1.09 g, 6.56 mmol-dissolved in 4 mL water)was added slowly at 0° C. After stirring at room temperature for 18hours, the reaction mixture was partitioned between ether and 10%aqueous sodium bisulfite solution. The ether layer was washed withwater, dried using anhydrous magnesium sulfate, filtered andconcentrated under reduced pressure. Purification of the residue bysilica gel column chromatography eluting with hexane yielded5-Iodo-2-isopropyl-1,3-dimethoxy-benzene (807 mg, 40%) as a white solid,MS (M+H)=307.

Step 8 5-Iodo-2-isopropyl-3-methoxy-phenol

To a solution of 5-Iodo-2-isopropyl-1,3-dimethoxy-benzene (805 mg, 2.63mmol) in anhydrous dichloromethane (26 mL) at 0° C. was added borontribromide (2.63 mL, 2.63 mmol) 1M in dichloromethane), maintaining thetemperature of the reaction at 0° C. during the addition. After stirringat room temperature for 18 hours, water (10 mL) was slowly added to thereaction. After stirring 30 minutes, the dichloromethane layer wascollected, dried using anhydrous magnesium sulfate, filtered andconcentrated under reduced pressure. Purification of the residue bysilica gel column chromatography eluting with 90/10 hexane/ethyl acetateyielded 5-Iodo-2-isopropyl-3-methoxy-phenol (612 mg, 80%) as an oil, MS(M+H)=293.

Step 9 5-(5-Iodo-2-isopropyl-3-methoxy-phenoxy)-pyrimidine-2,4-diamine

Following the procedure of Steps 2-4 of Example 6,5-Iodo-2-isopropyl-3-methoxy-phenol was converted to5-(5-Iodo-2-isopropyl-3-methoxy-phenoxy)-pyrimidine-2,4-diamine, MS(M+H)=401.

Example 10

Formulations

Pharmaceutical preparations for delivery by various routes areformulated as shown in the following Tables. “Active ingredient” or“Active compound” as used in the Tables means one or more of theCompounds of Formula I. Composition for Oral Administration Ingredient %wt./wt. Active ingredient 20.0% Lactose 79.5% Magnesium stearate 0.5%

The ingredients are mixed and dispensed into capsules containing about100 mg each; one capsule would approximate a total daily dosage.Composition for Oral Administration Ingredient % wt./wt. Activeingredient 20.0% Magnesium stearate 0.5% Crosscarmellose sodium 2.0%Lactose 76.5% PVP (polyvinylpyrrolidine) 1.0%

The ingredients are combined and granulated using a solvent such asmethanol. The formulation is then dried and formed into tablets(containing about 20 mg of active compound) with an appropriate tabletmachine. Composition for Oral Administration Ingredient Amount Activecompound 1.0 g Fumaric acid 0.5 g Sodium chloride 2.0 g Methyl paraben0.15 g Propyl paraben 0.05 g Granulated sugar 25.5 g Sorbitol (70%solution) 12.85 g Veegum K (Vanderbilt Co.) 1.0 g Flavoring 0.035 mlColorings 0.5 mg Distilled water q.s. to 100 ml

The ingredients are mixed to form a suspension for oral administration.Parenteral Formulation Ingredient % wt./wt. Active ingredient 0.25 gSodium Chloride qs to make isotonic Water for injection 100 ml

The active ingredient is dissolved in a portion of the water forinjection. A sufficient quantity of sodium chloride is then added withstirring to make the solution isotonic. The solution is made up toweight with the remainder of the water for injection, filtered through a0.2 micron membrane filter and packaged under sterile conditions.Suppository Formulation Ingredient % wt./wt. Active ingredient 1.0%Polyethylene glycol 1000 74.5% Polyethylene glycol 4000 24.5%

The ingredients are melted together and mixed on a steam bath, andpoured into molds containing 2.5 g total weight. Topical FormulationIngredients Grams Active compound 0.2-2 Span 60 2 Tween 60 2 Mineral oil5 Petrolatum 10 Methyl paraben 0.15 Propyl paraben 0.05 BHA (butylatedhydroxy anisole) 0.01 Water q.s. 100

All of the ingredients, except water, are combined and heated to about60° C. with stirring. A sufficient quantity of water at about 60° C. isthen added with vigorous stirring to emulsify the ingredients, and waterthen added q.s. about 100 g.

Nasal Spray Formulations

Several aqueous suspensions containing from about 0.025-0.5 percentactive compound are prepared as nasal spray formulations. Theformulations optionally contain inactive ingredients such as, forexample, microcrystalline cellulose, sodium carboxymethylcellulose,dextrose, and the like. Hydrochloric acid may be added to adjust pH. Thenasal spray formulations may be delivered via a nasal spray metered pumptypically delivering about 50-100 microliters of formulation peractuation. A typical dosing schedule is 2-4 sprays every 4-12 hours.

Example 11 P2X₃/P2X_(2/3) FLIPR (Fluorometric Imaging Plate Reader)Assay

CHO-K1 cells were transfected with cloned rat P2X₃ or human P2X_(2/3)receptor subunits and passaged in flasks. 18-24 hours before the FLIPRexperiment, cells were released from their flasks, centrifuged, andresuspended in nutrient medium at 2.5×10⁵ cells/ml. The cells werealiquoted into black-walled 96-well plates at a density of 50,000cells/well and incubated overnight in 5% CO₂ at 37° C. On the day of theexperiment, cells were washed in FLIPR buffer (calcium- andmagnesium-free Hank's balanced salt solution, 10 mM HEPES, 2 mM CaCl₂,2.5 mM probenecid; FB). Each well received 100 μl FB and 100 μl of thefluorescent dye Fluo-3 AM [2 μM final conc.]. After a 1 hour dye loadingincubation at 37° C., the cells were washed 4 times with FB, and a final75 μl/well FB was left in each well.

Test compounds (dissolved in DMSO at 10 mM and serially diluted with FB)or vehicle were added to each well (25 μl of a 4× solution) and allowedto equilibrate for 20 minutes at room temperature. The plates were thenplaced in the FLIPR and a baseline fluorescence measurement (excitationat 488 nm and emission at 510-570 nm) was obtained for 10 seconds beforea 100 μl/well agonist or vehicle addition. The agonist was a 2× solutionof α,β-meATP producing a final concentration of 1 μM (P2X₃) or 5 μM(P2X_(2/3)). Fluorescence was measured for an additional 2 minutes at 1second intervals after agonist addition. A final addition of ionomycin(5 μM, final concentration) was made to each well of the FLIPR testplate to establish cell viability and maximum fluorescence of dye-boundcytosolic calcium. Peak fluorescence in response to the addition ofα,β-meATP (in the absence and presence of test compounds) was measuredand inhibition curves generated using nonlinear regression. PPADS, astandard P2X antagonist, was used as a positive control.

Using the above procedure, compounds of the invention exhibited activityfor the P2X₃ and P2X_(2/3) receptor. The compound4-(2,4-Diamino-pyrimidin-5-yloxy)-2-ethynyl-5-isopropyl-phenol, forexample, exhibited a pIC₅₀ of approximately 8.24 for the P2X₃ receptor,and approximately 7.99 for the P2X_(2/3) receptor, using the aboveassay.

Example 12 In Vivo Assay for Asthma and Lung Function

BALb/cJ mice are immunized with a standard immunization protocol.Briefly, mice (N=8/group) are immunized i.p. with ovalbumin (OVA; 10 μg)in alum on days 0 and 14. Mice are then challenged with aerosolized OVA(5%) on day 21 and 22. Animals receive vehicle (p.o.) or a compound ofthe invention (100 mg/kg p.o.) all starting on day 20.

Lung function is evaluated on day 23 using the Buxco system to measurePenH in response to an aerosol methacholine challenge. Mice are theneuthanized and plasma samples collected at the end of the study.

Example 13 Volume Induced Bladder Contraction Assay

Female Sprague-Dawley rats (200-300 g) were anesthetized with urethane(1.5 g/kg, sc). The animals were tracheotomized, and a carotid arteryand femoral vein were cannulated for blood pressure measurement and drugadministration, respectively. A laparotomy was performed and the ureterswere ligated and transected proximal to the ligation. The externalurethral meatus was ligated with silk suture and the urinary bladder wascannulated via the dome for saline infusion and bladder pressuremeasurement.

Following a 15-30 minute stabilization period the bladder was infusedwith room temperature saline at 100 μl/min until continuousvolume-induced bladder contractions (VIBCs) were observed. The infusionrate was then lowered to 3-5 μl/min for 30 minutes before the bladderwas drained and allowed to rest for 30 minutes. All subsequent infusionswere performed as indicated except the lower infusion rate wasmaintained for only 15 minutes instead of 30 minutes. Bladder fillingand draining cycles were repeated until the threshold volumes (TV; thevolume needed to trigger the first micturition bladder contraction)varied by less than 10% for two consecutive baselines and contractionfrequency was within 2 contractions for a 10 minute period following theslower infusion rate. Once reproducible TVs and VIBCs were establishedthe bladder was drained and the animal was dosed with drug or vehicle(0.5 ml/kg, i.v.) 3 minutes prior to the start of the next scheduledinfusion.

Example 14 Formalin Pain Assay

Male Sprague Dawley rats (180-220 g) are placed in individual Plexiglascylinders and allowed to acclimate to the testing environment for 30min. Vehicle, drug or positive control (morphine 2 mg/kg) isadministered subcutaneously at 5 ml/kg. 15 min post dosing, formalin (5%in 50 μl) is injected into plantar surface of the right hind paw using a26-gauge needle. Rats are immediately put back to the observationchamber. Mirrors placed around the chamber allow unhindered observationof the formalin-injected paw. The duration of nociphensive behavior ofeach animal is recorded by a blinded observer using an automatedbehavioral timer. Hindpaw licking and shaking/lifting are recordedseparately in 5 min bin, for a total of 60 min. The sum of time spentlicking or shaking in seconds from time 0 to 5 min is considered theearly phase, whereas the late phase is taken as the sum of seconds spentlicking or shaking from 15 to 40 min. A plasma sample is collected.

Example 15 Colon Pain Assay

Adult male Sprague-Dawley rats (350-425 g; Harlan, Indianapolis, Ind.)are housed 1-2 per cage in an animal care facility. Rats are deeplyanesthetized with pentobarbital sodium (45 mg/kg) administeredintraperitoneally. Electrodes are placed and secured into the externaloblique musculature for electromyographic (EMG) recording. Electrodeleads are tunneled subcutaneously and exteriorized at the nape of theneck for future access. After surgery, rats are housed separately andallowed to recuperate for 4-5 days prior to testing.

The descending colon and rectum are distended by pressure-controlledinflation of a 7-8 cm-long flexible latex balloon tied around a flexibletube. The balloon is lubricated, inserted into the colon via the anus,and anchored by taping the balloon catheter to the base of the tail.Colorectal distension (CRD) is achieved by opening a solenoid gate to aconstant pressure air reservoir. Intracolonic pressure is controlled andcontinuously monitored by a pressure control device. Response isquantified as the visceromotor response (VMR), a contraction of theabdominal and hindlimb musculature. EMG activity produced by contractionof the external oblique musculature is quantified using Spike2 software(Cambridge Electronic Design). Each distension trial lasts 60 sec, andEMG activity is quantified for 20 sec before distension (baseline),during 20 sec distension, and 20 sec after distention. The increase intotal number of recorded counts during distension above baseline isdefined as the response. Stable baseline responses to CRD (10, 20, 40and 80 mmHg, 20 seconds, 4 minutes apart) are obtained in conscious,unsedated rats before any treatment.

Compounds are evaluated for effects on responses to colon distensioninitially in a model of acute visceral nociception and a model of colonhypersensitivity produced by intracolonic treatment with zymosan (1 mL,25 mg/mL) instilled into the colon with a gavage needle inserted to adepth of about 6 cm. Experimental groups will consist of 8 rats each.

Acute visceral nociception: For testing effects of drug on acutevisceral nociception, 1 of 3 doses of drug, vehicle or positive control(morphine, 2.5 mg/kg) are administered after baseline responses areestablished; responses to distension are followed over the next 60-90minutes.

Visceral hypersensitivity: For testing effects of drug or vehicle afterintracolonic treatment with zymosan, intracolonic treatment is givenafter baseline responses are established. Prior to drug testing at 4hours, responses to distension are assessed to establish the presence ofhypersensitivity. In zymosan-treated rats, administration of 1 of 3doses of drug, vehicle or positive control (morphine, 2.5 mg/kg) aregiven 4 hours after zymosan treatment and responses to distensionfollowed over the next 60-90 minutes.

Example 16 Cold allodynia in Rats with a Chronic Constriction Injury ofthe Sciatic Nerve

The effects of compounds of this invention on cold allodynia aredetermined using the chronic constriction injury (CCI) model ofneuropathic pain in rats, where cold allodynia is measured in acold-water bath with a metal-plate floor and water at a depth of 1.5-2.0cm and a temperature of 3-4° C. (Gogas, K. R. et al., Analgesia, 1997,3, 1-8).

Specifically, CCI, rats are anesthetized; the trifurcation of thesciatic nerve is located and 4 ligatures (4-0, or 5-0 chromic gut) areplaced circumferentially around the sciatic nerve proximal to thetrifurcation. The rats are then allowed to recover from the surgery. Ondays 4-7 after surgery, the rats are initially assessed for cold-inducedallodynia by individually placing the animals in the cold-water bath andrecording the total lifts of the injured paw during a 1-min period oftime: The injured paw is lifted out of the water. Paw lifts associatedwith locomotion or body repositioning are not recorded. Rats thatdisplayed 5 lifts per min or more on day 4-7 following surgery areconsidered to exhibit cold allodynia and are used in subsequent studies.In the acute studies, vehicle, reference compound or compounds of thisinvention are administered subcutaneously (s.c.) 30 min before testing.The effects of repeated administration of the compounds of thisinvention on cold allodynia are determined 14, 20 or 38 h following thelast oral dose of the following regimen: oral (p.o.) administration ofvehicle, reference or a compound of this invention at −12 h intervals(BID) for 7 days.

Example 17 Cancer Bone Pain in C3H/HeJ Mice

The effects of compounds of this invention on bone pain are determinedbetween Day 7 to Day 18 following intramedullary injection of 2472sarcoma cells into the distal femur of C3H/HeJ mice.

Specifically, NCTC 2472 tumor cells (American Type Culture Collection,ATCC), previously shown to form lytic lesions in bone afterintramedullary injection, are grown and maintained according to ATCCrecommendations. Approximately 10⁵ cells are injected directly into themedullary cavity of the distal femur in anesthetized C3H/HeJ mice.Beginning on about Day 7, the mice are assessed for spontaneousnocifensive behaviors (flinching & guarding), palpation-evokednocifensive behaviors (flinching & guarding), forced ambultory guardingand limb use. The effects of compounds of this invention are determinedfollowing a single acute (s.c.) administration on Day 7-Day 15. Inaddition, the effects of repeated (BID) administration of compounds ofthis invention from Day 7-Day 15 are determined within 1 hour of thefirst dose on Days 7, 9, 11, 13 and 15.

While the present invention has been described with reference to thespecific embodiments thereof, it should be understood by those skilledin the art that various changes may be made and equivalents may besubstituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto.

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein: X is: —CH₂—;—O—; —S(O)_(n)—; or —NR^(c)— wherein n is from 0 to 2 and R^(c) ishydrogen or alkyl; D is an optional oxygen; R¹ is: alkyl; alkenyl;cycloalkyl; cycloalkenyl; halo; haloalkyl; or hydroxyalkyl; R², R³, andR⁴ each independently is: hydrogen; alkyl; alkenyl; amino; halo; amido;haloalkyl; alkoxy; hydroxy; haloalkoxy; nitro; amino; hydroxyalkyl;alkoxyalkyl; hydroxyalkoxy; alkynylalkoxy; alkylsulfonyl; arylsulfonyl;cyano; aryl; heteroaryl; heterocyclyl; heterocyclylalkoxy; aryloxy;heteroaryloxy; aralkyloxy; heteroaralkyloxy; optionally substitutedphenoxy; —C≡C—R^(a); —(CH₂)_(m)-(Z)_(n)-(CO)—R^(b);—(CH₂)_(m)-(Z)_(n)-SO₂—(NR^(c))—R^(b) wherein m and n each independentlyis 0 or 1, Z is O or NR^(c), R^(a) is hydrogen; alkyl; aryl; aralkyl;heteroaryl; heteroaralkyl; hydroxyalkyl; alkoxyalkyl;alkylsulfonylalkyl; aminoalkyl; cyanoalkyl; alkylsilyl, cycloalkyl,cycloalkylalkyl; heterocycl; and heterocyclylalkyl; R^(b) is hydrogen,alkyl, hydroxy, alkoxy, amino, hydroxyalkyl or alkoxyalkyl, and eachR^(c) is independently hydrogen or alkyl; or R² and R³ together with theatoms to which they are attached may form a five or six-membered ringthat optionally includes one or two heteroatoms selected from O, S andN; R⁵ is: hydrogen; alkyl; aryl; aralkyl; heteroaryl; heteroaralkyl;hydroxyalkyl; alkoxyalkyl; alkylsulfonylalkyl; aminoalkyl; cyanoalkyl;alkylsilyl, cycloalkyl, cycloalkylalkyl; heterocycl; orheterocyclylalkyl; R⁶ is: hydrogen; alkyl; halo; haloalkyl; amino; oralkoxy; and R⁷ and R⁸ each independently is: hydrogen; alkyl;aminoalkyl; aminosulfonyl; cycloalkyl; cycloalkylalkyl; haloalkyl;haloalkoxy; hydroxyalky; alkoxyalkyl; alkylsulfonyl; alkylsulfonylalkyl;aminocarbonyloxyalkyl; hydroxycarbonylalkyl;hydroxyalkyloxycarbonylalkyl; aryl; aralkyl; arylsulfonyl; heteroaryl;heteroarylalkyl; heteroarylsulfonyl; heterocyclyl; or heterocyclylalkyl.2. The compound of claim 1, wherein R⁴ and R⁶ are hydrogen.
 3. Thecompound of claim 2, wherein R² is hydrogen.
 4. The compound of claim 3,wherein R¹ is ethyl, isopropyl, iodo, ethynyl or cyclopropyl.
 5. Thecompound of claim 4, wherein X is: —O—; or —CH₂—.
 6. The compound ofclaim 4, wherein R⁷ and R⁸ are hydrogen.
 7. The compound of claim 5,wherein one of R⁷ and R⁸ is hydrogen and the other is alkyl,hydroxyalkyl or haloalkyl.
 8. The compound of claim 6, wherein R³ is:hydrogen; halo; alkoxy; haloalkoxy; hydroxy; or alkylsulfonyl.
 9. Thecompound of claim 8, wherein R¹ is isopropyl.
 10. The compound of claim6, wherein R⁵ is: hydrogen; alkyl; optionally substituted phenyl;optionally substituted pyridinyl; optionally substituted thienyl;optionally substituted imidazolyl; hydroxyalkyl; alkoxyalkyl;aminoalkyl; cyanoalkyl; alkylsilyl or cycloalkyl.
 11. The compound ofclaim 6, wherein R⁵ is hydrogen or alkyl.
 12. The compound of claim 9,wherein R⁵ is hydrogen or methyl.
 13. The compound of claim 6, whereinR⁵ is heteroaryl selected from pyridinyl, pyrimdinyl, thienyl, furanyl,imidazolyl, pyrazolyl and pyrrolyl.
 14. The compound of claim 6, whereinR⁵ is: hydrogen; methyl; ethyl; propyl; phenyl; methoxymethyl;pyridin-2-yl; pyridin-3-yl; pyridin-4-yl; 2-hydroxyethyl;3-hydroxypropyl; hydroxymenthyl; methylaminomethyl; 2-cyanoethyl;thien-3-yl; 1-methylimidazol-5-yl; trimethylsilyl; or cyclopropyl. 15.The compound of claim 1 wherein said compound is of the formula (II):

wherein: X is: —CH₂—; or —O—; R¹ is: alkyl; alkenyl; alkynyl;cycloalkyl; cycloalkenyl; or halo; R³ is: hydrogen; alkyl; alkenyl;amino; halo; amido; haloalkyl; alkoxy; hydroxy; haloalkoxy; nitro;amino; hydroxyalkyl; alkoxyalkyl; hydroxyalkoxy; alkynylalkoxy;alkylsulfonyl; arylsulfonyl; cyano; aryl; heteroaryl; heterocyclyl;heterocyclylalkoxy; aryloxy; heteroaryloxy; aralkyloxy;heteroaralkyloxy; optionally substituted phenoxy; —C≡C—R^(a);—(CH₂)_(m)-(Z)_(n)-(CO)—R^(b); —(CH₂)_(m)-(Z)_(n)-SO₂—(NR^(c))_(n)—R^(b)wherein m and n each independently is 0 or 1, Z is O or NR^(c), R^(a) ishydrogen; alkyl; aryl; aralkyl; heteroaryl; heteroaralkyl; hydroxyalkyl;alkoxyalkyl; alkylsulfonylalkyl; aminoalkyl; cyanoalkyl; alkylsilyl,cycloalkyl, cycloalkylalkyl; heterocycl; and heterocyclylalkyl; R^(b) ishydrogen, alkyl, hydroxy, alkoxy, amino, hydroxyalkyl or alkoxyalkyl,and each R^(c) is independently hydrogen or alkyl; R⁵ is: hydrogen;alkyl; aryl; aralkyl; heteroaryl; heteroaralkyl; hydroxyalkyl;alkoxyalkyl; alkylsulfonylalkyl; aminoalkyl; cyanoalkyl; alkylsilyl,cycloalkyl, cycloalkylalkyl; heterocycl; or heterocyclylalkyl; and R⁷and R⁸ each independently is: hydrogen; alkyl; cycloalkyl;cycloalkylalkyl; haloalkyl; hydroxyalky; alkoxyalkyl; alkylsulfonyl;alkylsulfonylalkyl; aminocarbonyloxyalkyl; hydroxycarbonylalkyl;hydroxyalkyloxycarbonylalkyl; aryl; aralkyl; arylsulfonyl; heteroaryl;heteroarylalkyl; heteroarylsulfonyl; heterocyclyl; or heterocyclylalkyl.16. The compound of claim 1, wherein said compound is of the formula(III):

wherein: R¹ is: ethyl; isopropyl; iodo; ethynyl; or cyclopropyl; R³ is:hydrogen; alkyl; alkenyl; halo; haloalkyl; alkoxy; hydroxy; haloalkoxy;alkylsulfonyl; cyano; or —C≡C—R^(a); wherein R^(a) is hydrogen; alkyl;aryl; aralkyl; heteroaryl; heteroaralkyl; hydroxyalkyl; alkoxyalkyl;alkylsulfonylalkyl; aminoalkyl; cyanoalkyl; alkylsilyl, cycloalkyl,cycloalkylalkyl; heterocycl; and heterocyclylalkyl; R⁵ is: hydrogen;alkyl; aryl; aralkyl; heteroaryl; heteroaralkyl; hydroxyalkyl;alkoxyalkyl; alkylsulfonylalkyl; aminoalkyl; cyanoalkyl; alkylsilyl,cycloalkyl, cycloalkylalkyl; heterocycl; or heterocyclylalkyl; R⁷ and R⁸each independently is: hydrogen; alkyl; cycloalkyl; cycloalkylalkyl;haloalkyl; hydroxyalky; or alkoxyalkyl.
 17. The compound of claim 1,wherein said compound is of the formula (IV):

wherein: R³ is: hydrogen; alkyl; alkenyl; halo; haloalkyl; alkoxy;hydroxy; haloalkoxy; alkylsulfonyl; cyano; or —C≡C—R^(a); wherein R^(a)is hydrogen; alkyl; aryl; aralkyl; heteroaryl; heteroaralkyl;hydroxyalkyl; alkoxyalkyl; alkylsulfonylalkyl; aminoalkyl; cyanoalkyl;alkylsilyl, cycloalkyl, cycloalkylalkyl; heterocycl; andheterocyclylalkyl; R⁵ is: hydrogen; alkyl; aryl; aralkyl; heteroaryl;heteroaralkyl; hydroxyalkyl; alkoxyalkyl; alkylsulfonylalkyl;aminoalkyl; cyanoalkyl; alkylsilyl, cycloalkyl, cycloalkylalkyl;heterocycl; or heterocyclylalkyl; and R⁷ and R⁸ each independently is:hydrogen; alkyl; cycloalkyl; cycloalkylalkyl; haloalkyl; hydroxyalky; oralkoxyalkyl.
 18. A compound of the formula (X):

or a pharmaceutically acceptable salt thereof, wherein: X is: —CH₂—;—O—; —S(O)_(n)—; or NR^(c)— wherein n is from 0 to 2 and R^(c) ishydrogen or alkyl; D is an optional oxygen; R¹ is: alkyl; alkenyl;cycloalkyl; cycloalkenyl; halo; haloalkyl; or hydroxyalkyl; R¹¹ is:alkyl; alkenyl; amino; halo; amido; haloalkyl; alkoxy; hydroxy;haloalkoxy; nitro; amino; hydroxyalkyl; alkoxyalkyl; hydroxyalkoxy;alkynylalkoxy; alkylsulfonyl; arylsulfonyl; cyano; aryl; heteroaryl;heterocyclyl; heterocyclylalkoxy; aryloxy; heteroaryloxy; aralkyloxy;heteroaralkyloxy; optionally substituted phenoxy; —C≡C—R^(a);—(CH₂)_(m)-(Z)_(n)-(CO)—R^(b); —(CH₂)_(m)-(Z)_(n)-SO₂—(NR^(c))_(n)—R^(b)wherein m and n each independently is 0 or 1, Z is O or NR^(c), R^(a) ishydrogen; alkyl; aryl; aralkyl; heteroaryl; heteroaralkyl; hydroxyalkyl;alkoxyalkyl; alkylsulfonylalkyl; aminoalkyl; cyanoalkyl; alkylsilyl,cycloalkyl, cycloalkylalkyl; heterocycl; and heterocyclylalkyl; R^(b) ishydrogen, alkyl, hydroxy, alkoxy, amino, hydroxyalkyl or alkoxyalkyl,and each R^(c) is independently hydrogen or alkyl; or R² and R³ togetherwith the atoms to which they are attached may form a five orsix-membered ring that optionally includes one or two heteroatomsselected from O, S and N; R¹² is alkoxy or hydroxy; and R⁷ and R⁸ eachindependently is: hydrogen; alkyl; cycloalkyl; cycloalkylalkyl;haloalkyl; haloalkoxy; hydroxyalky; alkoxyalkyl; alkylsulfonyl;alkylsulfonylalkyl; aminocarbonyloxyalkyl; hydroxycarbonylalkyl;hydroxyalkyloxycarbonylalkyl; aryl; aralkyl; arylsulfonyl; heteroaryl;heteroarylalkyl; heteroarylsulfonyl; heterocyclyl; or heterocyclylalkyl.19. A compound of the formula (VII):

or a pharmaceutically acceptable salt thereof, wherein: X is: —CH₂—;—O—; —S(O)_(n)—; or —NR^(c)— wherein n is from 0 to 2 and R^(c) ishydrogen or alkyl; D is an optional oxygen; R², R³, R⁴ and R¹⁰ eachindependently is: hydrogen; alkyl; alkenyl; amino; halo; amido;haloalkyl; alkoxy; hydroxy; haloalkoxy; nitro; amino; hydroxyalkyl;alkoxyalkyl; hydroxyalkoxy; alkynylalkoxy; alkylsulfonyl; arylsulfonyl;cyano; aryl; heteroaryl; heterocyclyl; heterocyclylalkoxy; aryloxy;heteroaryloxy; aralkyloxy; heteroaralkyloxy; optionally substitutedphenoxy; —C≡C—R^(a); —(CH₂)_(m)-(Z)_(n)-(CO)—R^(b);—(CH₂)_(m)-(Z)_(n)-SO₂—(NR^(c))_(n)—R^(b) wherein m and n eachindependently is 0 or 1, Z is O or NR^(c), R^(a) is hydrogen; alkyl;aryl; aralkyl; heteroaryl; heteroaralkyl; hydroxyalkyl; alkoxyalkyl;alkylsulfonylalkyl; aminoalkyl; cyanoalkyl; alkylsilyl, cycloalkyl,cycloalkylalkyl; heterocycl; and heterocyclylalkyl; R^(b) is hydrogen,alkyl, hydroxy, alkoxy, amino, hydroxyalkyl or alkoxyalkyl, and eachR^(c) is independently hydrogen or alkyl; or R² and R³ together with theatoms to which they are attached may form a five or six-membered ringthat optionally includes one or two heteroatoms selected from O, S andN; R⁶ is: hydrogen; alkyl; halo; haloalkyl; amino; or alkoxy; and R⁷ andR⁸ each independently is: hydrogen; alkyl; alkoxyalkyl; aminoalkyl;aminosulfonyl; cycloalkyl; cycloalkylalkyl; haloalkyl; haloalkoxy;hydroxyalky; alkoxyalkyl; alkylsulfonyl; alkylsulfonylalkyl;aminocarbonyloxyalkyl; hydroxycarbonylalkyl;hydroxyalkyloxycarbonylalkyl; aryl; aralkyl; arylsulfonyl; heteroaryl;heteroarylalkyl; heteroarylsulfonyl; heterocyclyl; or heterocyclylalkyl.20. A pharmaceutical composition comprising: (a) a pharmaceuticallyacceptable excipient; and (b) a compound of claim
 1. 21. A method fortreating a P2X₃ or P2X_(2/3) receptor antagonist-mediated urinary tractdisease selected from reduced bladder capacity, frequenct micturition,urge incontinence, stress incontinence, bladder hyperreactivity, benignprostatic hypertrophy, prostatitis, detrusor hyperreflexia, urinaryfrequency, nocturia, urinary urgency, overactive bladder, pelvichypersensitivity, urethritis, prostatitits, pelvic pain syndrome,prostatodynia, cystitis, or idiophatic bladder hypersensitivity, saidmethod comprising administering to a subject in need thereof aneffective amount of a compound of claim
 1. 22. A method for treating aP2X₃ or P2X_(2/3) receptor antagonist-mediated pain condition, said paincondition selected from inflammatory pain, surgical pain, visceral pain,dental pain, premenstrual pain, central pain, pain due to burns,migraine or cluster headaches, nerve injury, neuritis, neuralgias,poisoning, ischemic injury, interstitial cystitis, cancer pain, viral,parasitic or bacterial infection, post-traumatic injury, or painassociated with irritable bowel syndrome, said method comprisingadministering to a subject in need thereof an effective amount of acompound of claim
 1. 23. A method for treating a P2X₃ or P2X_(2/3)receptor antagonist-mediated respiratory disorder selected from chronicobstructive pulmonary disease, asthma, and bronchospasm, said methodcomprising administering to a subject in need thereof an effectiveamount of a compound of claim
 1. 24. A method for treating a P2X₃ orP2X_(2/3) receptor antagonist-mediated gastrointestinal disorderselected from irritable bowel syndrome, inflammatory bowel disease,biliary colic, renal colic, diarrhea-dominant IBS, and pain associatedwith gastrointestinal distension, said method comprising administeringto a subject in need thereof an effective amount of a compound of claim1.